Is PMS2 p.Ala38Ser (c.112G>T) pathogenic?

PMS2 p.Ala38Ser (c.112G>T) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-22). AlphaMissense: ambiguous (0.3628); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Ala38Ser (c.112G>T) in the general population?

PMS2 p.Ala38Ser (c.112G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PMS2 p.Ala38Ser (c.112G>T)?

AlphaMissense predicts ambiguous (score 0.3628) — an in-silico prediction, not a clinical call.

PMS2 p.Ala38Ser

Q: What condition is associated with PMS2 p.Ala38Ser (c.112G>T)?

PMS2 p.Ala38Ser (c.112G>T) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

c.112G>T · rs1554306427 · VCV455639

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3628 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.3628	ambiguous
REVEL	0.877	moderately pathogenic-leaning
SaProt	LLR -12.00	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	26.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PMS2
Protein: p.Ala38Ser
Coding: c.112G>T
MANE Select: NM_000535
dbSNP: rs1554306427
Type: single nucleotide variant
Location: chr7:6005943 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 38: an α-helix

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: hereditary neoplastic syndrome

Similar variants

PMS2 p.Ala38Glu Uncertain significance ★★ ⚠ same residue
PMS2 p.Ala38Thr Uncertain significance ★ ⚠ same residue
PMS2 p.Ala38Val Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Ala38= Likely benign ★ same residue
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-ala38ser (accessed [today's date]).

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