Is PMS2 p.Ala423Asp (c.1268C>A) pathogenic?

PMS2 p.Ala423Asp (c.1268C>A) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-04). AlphaMissense: likely benign (0.3259); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Ala423Asp (c.1268C>A)?

PMS2 p.Ala423Asp (c.1268C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Ala423Asp (c.1268C>A) in the general population?

PMS2 p.Ala423Asp (c.1268C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PMS2 p.Ala423Asp (c.1268C>A)?

AlphaMissense predicts likely benign (score 0.3259) — an in-silico prediction, not a clinical call.

PMS2 p.Ala423Asp

c.1268C>A · rs756883400 · VCV631290

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3259 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3259	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -6.95	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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) · 1/1,180,014 alleles

Overall 0.000124% 2/1,614,150 alleles · very rare exomes 2/1,461,864 · genomes 0/152,286 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
European (non-Finnish)grpmax	8.47e-05%	1,180,013

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala423Asp
Coding: c.1268C>A
MANE Select: NM_000535
dbSNP: rs756883400
Type: single nucleotide variant
Location: chr7:5987497 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 423: the 'disordered' region; a UniProt-annotated variant site (normal dna mismatch repair activity)

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

Similar variants

PMS2 p.Ala423Ser Uncertain significance ★★ ⚠ same residue
PMS2 p.Ala423Val Uncertain significance ★★ ⚠ same residue
PMS2 p.Ala423= Benign/Likely benign ★★ same residue
PMS2 p.Ala423Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Ala423Thr Uncertain significance ★ ⚠ 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

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-ala423asp (accessed [today's date]).

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