Is PMS2 p.Ser238Arg (c.714C>A) pathogenic?

PMS2 p.Ser238Arg (c.714C>A) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-01-18). AlphaMissense: likely pathogenic (0.7146); Ultra-rare (popmax 0.0347%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Ser238Arg (c.714C>A)?

PMS2 p.Ser238Arg (c.714C>A) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Ser238Arg (c.714C>A) in the general population?

PMS2 p.Ser238Arg (c.714C>A) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

What do computational predictors say about PMS2 p.Ser238Arg (c.714C>A)?

AlphaMissense predicts likely pathogenic (score 0.7146) — an in-silico prediction, not a clinical call.

PMS2 p.Ser238Arg

c.714C>A · rs151251082 · VCV93236

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.7146 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.7146	likely pathogenic
REVEL	0.57	indeterminate
SaProt	LLR -10.74	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	23.0	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 0.0347% African / African-American · 24/69,106 alleles

Filtering AF 0.0239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0203%

Overall 0.00193% 30/1,553,640 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,879
Remaining individualsnot grpmax-eligible	0.00494%	20,252
Admixed American	0.00361%	27,678
European (non-Finnish)	8.78e-05%	1,139,592

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.Ser238Arg
Coding: c.714C>A
MANE Select: NM_000535
dbSNP: rs151251082
Type: single nucleotide variant
Location: chr7:5997415 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 238: a UniProt-annotated variant site (in lynch4; uncertain significance; no effect on dna mismatch repair activity in an in vitro assay, compared to wild-type; no effect on atpase activity; no effect on protein stability)

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.Ser238Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser238Thr Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser238Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Ser238Cys Uncertain significance ★ ⚠ same residue
PMS2 p.Ser238Ile Uncertain significance ★ ⚠ same residue
PMS2 p.Ser238= Benign ★ same residue
PMS2 p.Ser238fs Pathogenic ★★ same residue
PMS2 c.1144+2T>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-ser238arg (accessed [today's date]).

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