Is PMS2 p.Thr277= (c.831G>A) pathogenic?

PMS2 p.Thr277= (c.831G>A) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-01-31). Ultra-rare (popmax 0.0428%, sas); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Thr277= (c.831G>A) in the general population?

PMS2 p.Thr277= (c.831G>A) is ultra-rare (popmax 0.0428%, sas) (gnomAD).

PMS2 p.Thr277=

Q: What condition is associated with PMS2 p.Thr277= (c.831G>A)?

PMS2 p.Thr277= (c.831G>A) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, breast cancer (ClinVar).

c.831G>A · rs116481522 · VCV185282

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0428%, sas)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.8
Overall
CADD	0.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0428% South Asian · 39/91,066 alleles

Filtering AF 0.0322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0284%

Overall 0.00539% 87/1,613,502 alleles · ultra-rare exomes 78/1,461,280 · genomes 9/152,222 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0428%	2,335
Remaining individualsnot grpmax-eligible	0.0096%	10,415
Admixed American	0.005%	19,991
European (non-Finnish)	0.00305%	32,763
East Asian	0.00223%	44,884
Finnishnot grpmax-eligible	0.00156%	64,022
African / African-American	0.00133%	75,016

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.Thr277=
Coding: c.831G>A
MANE Select: NM_000535
dbSNP: rs116481522
Type: single nucleotide variant
Location: chr7:5995606 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 277: a UniProt-annotated variant site (in)

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 breast cancer Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Thr277Ser Uncertain significance ★★ ⚠ same residue
PMS2 p.Thr277Arg Uncertain significance ★ ⚠ same residue
PMS2 p.Thr277Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Thr277Met Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Thr277Pro Uncertain significance ★ ⚠ same residue
PMS2 p.Thr277fs Pathogenic ★★ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.163+2T>C 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-thr277 (accessed [today's date]).

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