Is PMS2 p.Phe424Ser (c.1271T>C) pathogenic?

PMS2 p.Phe424Ser (c.1271T>C) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-11-30). AlphaMissense: likely pathogenic (0.8318); Very rare (popmax 8.47e-05%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Phe424Ser (c.1271T>C)?

PMS2 p.Phe424Ser (c.1271T>C) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Phe424Ser (c.1271T>C) in the general population?

PMS2 p.Phe424Ser (c.1271T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PMS2 p.Phe424Ser (c.1271T>C)?

AlphaMissense predicts likely pathogenic (score 0.8318) — an in-silico prediction, not a clinical call.

PMS2 p.Phe424Ser

c.1271T>C · rs876661186 · VCV234733

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.8318 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.8318	likely pathogenic
REVEL	0.315	indeterminate
SaProt	LLR -5.40	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	25.4	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 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.2e-05% 1/1,614,156 alleles · very rare exomes 1/1,461,866 · genomes 0/152,290 · joint denominator

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.Phe424Ser
Coding: c.1271T>C
MANE Select: NM_000535
dbSNP: rs876661186
Type: single nucleotide variant
Location: chr7:5987494 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 424: the 'disordered' region

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

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Phe424Ile Uncertain significance ★★ ⚠ same residue
PMS2 p.Phe424Leu Uncertain significance ★★ ⚠ 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
PMS2 c.251-2A>G 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-phe424ser (accessed [today's date]).

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