Is PMS2 p.Ala38Val (c.113C>T) pathogenic?

PMS2 p.Ala38Val (c.113C>T) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-02-03). AlphaMissense: ambiguous (0.4065); Ultra-rare (popmax 0.0167%, amr); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Ala38Val (c.113C>T) in the general population?

PMS2 p.Ala38Val (c.113C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about PMS2 p.Ala38Val (c.113C>T)?

AlphaMissense predicts ambiguous (score 0.4065) — an in-silico prediction, not a clinical call.

PMS2 p.Ala38Val

Q: What condition is associated with PMS2 p.Ala38Val (c.113C>T)?

PMS2 p.Ala38Val (c.113C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 4 (ClinVar).

c.113C>T · rs148270248 · VCV187605

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

ambiguous

0.4065 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.4065	ambiguous
REVEL	0.699	pathogenic-leaning
SaProt	LLR -9.76	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	31.0	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 0.0167% Admixed American · 10/59,996 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00174% 28/1,610,778 alleles · ultra-rare exomes 20/1,458,528 · genomes 8/152,250 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,000
South Asian	0.00769%	12,998
African / African-American	0.00267%	37,474
East Asian	0.00223%	44,868
European (non-Finnish)	0.000678%	147,478

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.Ala38Val
Coding: c.113C>T
MANE Select: NM_000535
dbSNP: rs148270248
Type: single nucleotide variant
Location: chr7:6005942 (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: Lynch syndrome Lynch syndrome 4 hereditary neoplastic syndrome mismatch repair cancer syndrome 4

Similar variants

PMS2 p.Ala38Glu Uncertain significance ★★ ⚠ same residue
PMS2 p.Ala38Ser Uncertain significance ★★ ⚠ same residue
PMS2 p.Ala38Thr Uncertain significance ★ ⚠ same residue
PMS2 p.Ala38= Likely benign ★ 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

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-ala38val (accessed [today's date]).

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