Is PMS2 p.Gln205Pro (c.614A>C) pathogenic?

PMS2 p.Gln205Pro (c.614A>C) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 20 submitters; last evaluated 2026-01-22). AlphaMissense: likely pathogenic (0.7373); Very rare (popmax 0.005%, nfe); Associated with Lynch syndrome.

What condition is associated with PMS2 p.Gln205Pro (c.614A>C)?

PMS2 p.Gln205Pro (c.614A>C) is associated with Lynch syndrome, colon carcinoma, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Gln205Pro (c.614A>C) in the general population?

PMS2 p.Gln205Pro (c.614A>C) is very rare (popmax 0.005%, nfe) (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PMS2 p.Gln205Pro (c.614A>C)?

AlphaMissense predicts likely pathogenic (score 0.7373) — an in-silico prediction, not a clinical call.

PMS2 p.Gln205Pro

c.614A>C · rs587779342 · VCV91361

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 20 submitters

AlphaMissense

likely pathogenic

0.7373 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome

ClinGen expert panel — InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Uncertain Significance for colorectal cancer, hereditary nonpolyposis, type 4. Applied ACMG criteria (verbatim):

PP3 PP4 PM3

Curation rationale (ClinGen, verbatim)

The NM_000535.7: c.614A>C variant in PMS2 is a missense variant predicted to cause substitution of Glutamin by Prolin at amino acid 205 (p.Gln205Pro). This alteration was detected in trans with a mutation in PMS2 (c.1A>G) in an individual meeting the clinical criteria for CMMR-D (≥3 points, table 3 of the ClinGen_InSiGHTColorectalCancer/Polyposis_ACMG_Specifications_v1), (PM3 met). The Frequency of this variant in gnomAD V4.1.0 is 0.000037 (0.0037%), which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP threshold (<1 in 50,000 alleles) for PM2_supporting, and therefore PM2_supporting is not met. The variant was detected in at least one CRC/Endometrial MSI-H tumour using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location (PP4). This missense variant mets the criteria for PP3 (MAPP+PolyPhen-2 prior probability for pathogenicity >0.68 & ≤0.81). Due to insufficient evidence, this variant is classified as a variant of uncertain significance for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PM3, PP3, PP4 (VCEP specifications version 1)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.7373	likely pathogenic
REVEL	0.823	moderately pathogenic-leaning
SaProt	LLR -15.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% European (non-Finnish) · 59/1,179,988 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00372% 60/1,614,082 alleles · very rare exomes 60/1,461,838 · genomes 0/152,244 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.005%	20,000
Remaining individualsnot grpmax-eligible	0.0016%	62,494

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PMS2
Protein: p.Gln205Pro
Coding: c.614A>C
MANE Select: NM_000535
dbSNP: rs587779342
Type: single nucleotide variant
Location: chr7:5999199 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 205: a UniProt-annotated variant site (in mmrcs4 and lynch4; uncertain significance; normal dna mismatch repair activity); a β-strand

Full PMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Lynch syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colon carcinoma Lynch syndrome 4 hereditary neoplastic syndrome hereditary nonpolyposis colon cancer

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Gln205Ter Pathogenic/Likely pathogenic ★★ same residue
PMS2 p.Gln205Glu Uncertain significance ★★ ⚠ same residue
PMS2 p.Gln205His Uncertain significance ★★ ⚠ same residue
PMS2 p.Gln205Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Gln205Lys Uncertain significance ★★ ⚠ same residue
PMS2 p.Gln205= Benign/Likely benign ★★ same residue
PMS2 p.Gln205Arg Uncertain significance ★ ⚠ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pms2-p-gln205pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown