Is PMS2 p.Lys301= (c.903G>A) pathogenic?

PMS2 p.Lys301= (c.903G>A) is classified Pathogenic/Likely pathogenic in PMS2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-12). Very rare (popmax 0.000425%, nfe); Associated with hereditary nonpolyposis colon cancer.

What condition is associated with PMS2 p.Lys301= (c.903G>A)?

PMS2 p.Lys301= (c.903G>A) is associated with hereditary nonpolyposis colon cancer, Lynch syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Lys301= (c.903G>A) in the general population?

PMS2 p.Lys301= (c.903G>A) is very rare (popmax 0.000425%, nfe) (gnomAD).

PMS2 p.Lys301=

c.903G>A · rs267608153 · VCV237932

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000425%, nfe)

Conditions

hereditary nonpolyposis colon cancer

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.70	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.60	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.9	phastCons 1
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000425% European (non-Finnish) · 5/1,176,072 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000311% 5/1,609,560 alleles · very rare exomes 4/1,457,502 · genomes 1/152,058 · joint denominator

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.Lys301=
Coding: c.903G>A
MANE Select: NM_000535
dbSNP: rs267608153
Type: single nucleotide variant
Location: chr7:5995534 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 301: an α-helix

Full PMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary nonpolyposis colon cancer — 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.Lys301Glu Uncertain significance ★★ ⚠ same residue
PMS2 p.Lys301Arg Uncertain significance ★ ⚠ same residue
PMS2 p.Lys301Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Lys301Thr Uncertain significance ★ ⚠ same residue
PMS2 p.Lys301Ter Pathogenic ★ 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

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-lys301 (accessed [today's date]).

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