Is PMS2 p.Phe751= (c.2253T>C) pathogenic?

PMS2 p.Phe751= (c.2253T>C) is classified Benign in PMS2 (ClinVar, Expert panel, 23 submitters; last evaluated 2013-09-05). Ultra-rare (popmax 0.042%, afr); Associated with Lynch syndrome.

What condition is associated with PMS2 p.Phe751= (c.2253T>C)?

PMS2 p.Phe751= (c.2253T>C) is associated with Lynch syndrome, endometrial carcinoma, Lynch syndrome 1 (ClinVar).

How common is PMS2 p.Phe751= (c.2253T>C) in the general population?

PMS2 p.Phe751= (c.2253T>C) is ultra-rare (popmax 0.042%, afr) (gnomAD).

How is Lynch syndrome inherited?

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

PMS2 p.Phe751=

c.2253T>C · rs1805325 · VCV36688

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 23 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.042%, afr)

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 2.6	phastCons 1
Overall
CADD	9.286	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.042% African / African-American · 31/73,852 alleles

Filtering AF 0.0304% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0264%

Overall 0.0371% 595/1,603,588 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.32%	76
Remaining individualsnot grpmax-eligible	0.0887%	1,128
African / African-Americangrpmax	0.042%	2,382
East Asian	0.0157%	6,354
European (non-Finnish)	0.00878%	11,392
Finnishnot grpmax-eligible	0.00791%	12,648
South Asian	0.00662%	15,102
Admixed American	0.00502%	19,937

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe751=
Coding: c.2253T>C
MANE Select: NM_000535
dbSNP: rs1805325
Type: single nucleotide variant
Location: chr7:5978618 (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

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

Also linked: endometrial carcinoma Lynch syndrome 1 Lynch syndrome 4 hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Phe751Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Phe751Ile Uncertain significance ★ ⚠ same residue
PMS2 p.Phe751Ser 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
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-phe751 (accessed [today's date]).

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