Is PMS2 p.Val214= (c.642G>A) pathogenic?

PMS2 p.Val214= (c.642G>A) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-08). Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Val214= (c.642G>A)?

PMS2 p.Val214= (c.642G>A) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Val214= (c.642G>A) in the general population?

PMS2 p.Val214= (c.642G>A) is absent from gnomAD v4.1 (gnomAD).

PMS2 p.Val214=

c.642G>A · rs2128800346 · VCV1082333

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.20	donor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.12	phastCons 0.004
Overall
CADD	8.435	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PMS2
Protein: p.Val214=
Coding: c.642G>A
MANE Select: NM_000535
dbSNP: rs2128800346
Type: single nucleotide variant
Location: chr7:5999171 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 214: a β-strand

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

Similar variants

PMS2 p.Val214Ala Uncertain significance ★★ ⚠ same residue
PMS2 p.Val214Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Val214Met Uncertain significance ★★ ⚠ same residue
PMS2 p.Val214Leu Uncertain significance ★ ⚠ 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-val214 (accessed [today's date]).

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