Is PMS2 p.Phe778= (c.2334C>T) pathogenic?

PMS2 p.Phe778= (c.2334C>T) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-05). Very rare (popmax 0.00836%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Phe778= (c.2334C>T)?

PMS2 p.Phe778= (c.2334C>T) is associated with hereditary neoplastic syndrome, breast cancer, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Phe778= (c.2334C>T) in the general population?

PMS2 p.Phe778= (c.2334C>T) is very rare (popmax 0.00836%, amr) (gnomAD).

PMS2 p.Phe778=

c.2334C>T · rs768674294 · VCV379017

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00836%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.362	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.071	phastCons 0.011
Overall
CADD	9.561	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00836% Admixed American · 5/59,804 alleles

Filtering AF 0.0035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0024%

Overall 0.0028% 45/1,606,344 alleles · very rare exomes 38/1,455,890 · genomes 7/150,454 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00836%	11,961
African / African-American	0.00809%	12,367
South Asian	0.00331%	30,211
European (non-Finnish)	0.00255%	39,164
Remaining individualsnot grpmax-eligible	0.00161%	62,212

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.Phe778=
Coding: c.2334C>T
MANE Select: NM_000535
dbSNP: rs768674294
Type: single nucleotide variant
Location: chr7:5977699 (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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: breast cancer Lynch syndrome 4

Similar variants

PMS2 p.Phe778Ile Uncertain significance ★★ ⚠ same residue
PMS2 p.Phe778Cys Uncertain significance ★ ⚠ same residue
PMS2 p.Phe778fs Pathogenic ★ same residue
PMS2 p.Phe778Leu 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-phe778 (accessed [today's date]).

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