Is PMS2 p.Lys413= (c.1239A>G) pathogenic?

PMS2 p.Lys413= (c.1239A>G) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-01-30). Ultra-rare (popmax 0.0329%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Lys413= (c.1239A>G)?

PMS2 p.Lys413= (c.1239A>G) is associated with hereditary neoplastic syndrome, Lynch syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Lys413= (c.1239A>G) in the general population?

PMS2 p.Lys413= (c.1239A>G) is ultra-rare (popmax 0.0329%, sas) (gnomAD).

PMS2 p.Lys413=

c.1239A>G · rs1244752544 · VCV1405851

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.5
Overall
CADD	1.747	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% South Asian · 30/91,048 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.00304% 49/1,613,372 alleles · ultra-rare exomes 41/1,461,508 · genomes 8/151,864 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0329%	3,035
Remaining individualsnot grpmax-eligible	0.0064%	15,620
African / African-American	0.00535%	18,706
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
European (non-Finnish)	0.000848%	117,965

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.Lys413=
Coding: c.1239A>G
MANE Select: NM_000535
dbSNP: rs1244752544
Type: single nucleotide variant
Location: chr7:5987526 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 413: the 'disordered' region

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

Disease context

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

Also linked: Lynch syndrome Lynch syndrome 4

Similar variants

PMS2 p.Lys413Asn Uncertain significance ★★ ⚠ same residue
PMS2 p.Lys413Glu Uncertain significance ★ ⚠ same residue
PMS2 p.Lys413Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Lys413fs Pathogenic ★ same residue
PMS2 p.Lys413_Asp414insLys Uncertain significance ★ same residue
PMS2 p.Lys413Arg Conflicting classifications of pathogenicity ★ same residue
PMS2 p.Lys413del Pathogenic 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-lys413 (accessed [today's date]).

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