Is PMS2 p.Arg421Gln (c.1262G>A) pathogenic?

PMS2 p.Arg421Gln (c.1262G>A) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.17); Ultra-rare (popmax 0.0329%, mid); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Arg421Gln (c.1262G>A)?

PMS2 p.Arg421Gln (c.1262G>A) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Arg421Gln (c.1262G>A) in the general population?

PMS2 p.Arg421Gln (c.1262G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about PMS2 p.Arg421Gln (c.1262G>A)?

AlphaMissense predicts likely benign (score 0.17) — an in-silico prediction, not a clinical call.

PMS2 p.Arg421Gln

c.1262G>A · rs778482303 · VCV411047

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.17 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.17	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -5.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
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	27.3	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00143% 23/1,614,008 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Admixed American	0.00334%	29,984
East Asian	0.00223%	44,892
South Asian	0.0022%	45,542
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.00127%	78,669

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.Arg421Gln
Coding: c.1262G>A
MANE Select: NM_000535
dbSNP: rs778482303
Type: single nucleotide variant
Location: chr7:5987503 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 421: 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 4 hereditary neoplastic syndrome mismatch repair cancer syndrome 4

Similar variants

PMS2 p.Arg421Ter Pathogenic ★★★ same residue
PMS2 p.Arg421Leu Uncertain significance ★★ same residue
PMS2 p.Arg421Pro Uncertain significance ★ ⚠ same residue
PMS2 p.Arg421= 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-arg421gln (accessed [today's date]).

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