Is PMS2 p.Pro404Arg (c.1211C>G) pathogenic?

PMS2 p.Pro404Arg (c.1211C>G) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 21 submitters; last evaluated 2026-01-30). AlphaMissense: likely benign (0.0818); Ultra-rare (popmax 0.0362%, sas); Associated with PMS2-related disorder.

What condition is associated with PMS2 p.Pro404Arg (c.1211C>G)?

PMS2 p.Pro404Arg (c.1211C>G) is associated with PMS2-related disorder, Lynch syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Pro404Arg (c.1211C>G) in the general population?

PMS2 p.Pro404Arg (c.1211C>G) is ultra-rare (popmax 0.0362%, sas) (gnomAD).

What do computational predictors say about PMS2 p.Pro404Arg (c.1211C>G)?

AlphaMissense predicts likely benign (score 0.0818) — an in-silico prediction, not a clinical call.

PMS2 p.Pro404Arg

c.1211C>G · rs536111818 · VCV142875

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 21 submitters

AlphaMissense

likely benign

0.0818 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0362%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PMS2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0818	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	19.07	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 0.0362% South Asian · 33/91,082 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0231%

Overall 0.0103% 166/1,613,884 alleles · ultra-rare exomes 157/1,461,650 · genomes 9/152,234 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0362%	2,760
Middle Eastern	0.0165%	6,060
European (non-Finnish)	0.0106%	9,439
Admixed American	0.00667%	14,995
Remaining individualsnot grpmax-eligible	0.0048%	20,834

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.Pro404Arg
Coding: c.1211C>G
MANE Select: NM_000535
dbSNP: rs536111818
Type: single nucleotide variant
Location: chr7:5987554 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 404: the 'disordered' region

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

Disease context

PMS2-related disorder

Also linked: Lynch syndrome Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Pro404Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro404Ser Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro404= Conflicting classifications of pathogenicity ★ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.163+2T>C Likely pathogenic ★★★ same condition
PMS2 c.164-2A>G Likely pathogenic ★★★ same condition
PMS2 c.2007-1G>A Likely pathogenic ★★★ same condition
PMS2 c.2174+1G>A 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-pro404arg (accessed [today's date]).

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