Is PMS2 p.His496= (c.1488C>T) pathogenic?

PMS2 p.His496= (c.1488C>T) is classified Benign in PMS2 (ClinVar, Expert panel, 23 submitters; last evaluated 2013-09-05). Common (popmax 7.49%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Lynch syndrome.

What condition is associated with PMS2 p.His496= (c.1488C>T)?

PMS2 p.His496= (c.1488C>T) is associated with Lynch syndrome, breast cancer, Lynch syndrome 4 (ClinVar).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

PMS2 p.His496=

Q: How common is PMS2 p.His496= (c.1488C>T) in the general population?

PMS2 p.His496= (c.1488C>T) is common (popmax 7.49%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1488C>T · rs1805320 · VCV91304

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 23 submitters

gnomAD v4.1

Common

common (popmax 7.49%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Lynch syndrome

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 -4.5
Overall
CADD	0.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.49% African / African-American · 5,605/74,846 alleles

Filtering AF 7.32% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.26%

Overall 0.412% 6,656/1,613,848 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.49%	13
Middle Eastern	0.677%	148
Remaining individualsnot grpmax-eligible	0.629%	159
Admixed American	0.593%	168
South Asian	0.0296%	3,374
European (non-Finnish)	0.0193%	5,175
Finnishnot grpmax-eligible	0.00781%	12,799
East Asian	0.00223%	44,878

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.His496=
Coding: c.1488C>T
MANE Select: NM_000535
dbSNP: rs1805320
Type: single nucleotide variant
Location: chr7:5987277 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 496: the 'disordered' region

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

Disease context

Lynch syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: breast cancer Lynch syndrome 4 hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.His496Gln Uncertain significance ★★ ⚠ same residue
PMS2 p.His496Tyr Uncertain significance ★ ⚠ same residue
PMS2 p.His496fs Pathogenic ★ same residue
PMS2 p.His496Asn 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-his496 (accessed [today's date]).

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