Is PMS2 p.Phe320Cys (c.959T>G) pathogenic?

PMS2 p.Phe320Cys (c.959T>G) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-19). AlphaMissense: ambiguous (0.4791); Very rare (popmax 8.57e-05%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Phe320Cys (c.959T>G) in the general population?

PMS2 p.Phe320Cys (c.959T>G) is very rare (popmax 8.57e-05%, nfe) (gnomAD).

What do computational predictors say about PMS2 p.Phe320Cys (c.959T>G)?

AlphaMissense predicts ambiguous (score 0.4791) — an in-silico prediction, not a clinical call.

PMS2 p.Phe320Cys

Q: What condition is associated with PMS2 p.Phe320Cys (c.959T>G)?

PMS2 p.Phe320Cys (c.959T>G) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

c.959T>G · rs1060503121 · VCV411035

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4791 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.57e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.4791	ambiguous
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -9.47	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
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	27.0	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 8.57e-05% European (non-Finnish) · 1/1,166,510 alleles

Overall 6.91e-05% 1/1,447,018 alleles · very rare

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.Phe320Cys
Coding: c.959T>G
MANE Select: NM_000535
dbSNP: rs1060503121
Type: single nucleotide variant
Location: chr7:5992002 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB

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: hereditary neoplastic syndrome

Similar variants

PMS2 p.Phe320Ser Uncertain significance ★★ ⚠ same residue
PMS2 p.Phe320Leu Uncertain significance ★ ⚠ same residue
PMS2 p.Phe320Tyr Uncertain significance ★ ⚠ same residue
PMS2 p.Phe320fs Pathogenic/Likely pathogenic ★★ 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
PMS2 c.2174+1G>A 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-phe320cys (accessed [today's date]).

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