Is EPCAM p.Pro84Ser (c.250C>T) pathogenic?

EPCAM p.Pro84Ser (c.250C>T) is classified Uncertain significance in EPCAM (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-01). AlphaMissense: likely pathogenic (0.7453); Ultra-rare (popmax 0.0735%, eas); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with EPCAM p.Pro84Ser (c.250C>T)?

EPCAM p.Pro84Ser (c.250C>T) is associated with hereditary breast ovarian cancer syndrome (ClinVar).

How common is EPCAM p.Pro84Ser (c.250C>T) in the general population?

EPCAM p.Pro84Ser (c.250C>T) is ultra-rare (popmax 0.0735%, eas) (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

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

What do computational predictors say about EPCAM p.Pro84Ser (c.250C>T)?

AlphaMissense predicts likely pathogenic (score 0.7453) — an in-silico prediction, not a clinical call.

EPCAM p.Pro84Ser

c.250C>T · rs139208605 · VCV830295

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7453 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0735%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.7453	likely pathogenic
REVEL	0.425	indeterminate
SaProt	LLR -4.40	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.4, phastCons 1
Regional constraint	o/e 1.32	unconstrained · MANE · 17 kb · p 4.4e-10 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0735% East Asian · 33/44,894 alleles

Filtering AF 0.0537% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.047%

Overall 0.00229% 37/1,613,864 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0735%	1,360
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.000169%	590,016

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: EPCAM
Protein: p.Pro84Ser
Coding: c.250C>T
MANE Select: NM_002354
dbSNP: rs139208605
Type: single nucleotide variant
Location: chr2:47373873 (GRCh38)
Gene constraint: LOEUF 1.341 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.71 · 2 PDB
Residue 84: a disulfide bond; a UniProt-annotated variant site (in diar5; likely pathogenic); an α-helix; the thyroglobulin type-1 domain

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

Disease context

hereditary breast ovarian cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

EPCAM p.Pro84Arg Uncertain significance ★ ⚠ same residue
EPCAM p.Asp130Tyr Uncertain significance ★ ⚠ same condition
EPCAM p.Val212Gly Uncertain significance ★ ⚠ same condition
EPCAM c.491+1G>A Pathogenic ★★ same type
EPCAM c.492-2A>G Pathogenic ★★ same type
EPCAM c.556-14A>G Pathogenic/Likely pathogenic ★★ same type
EPCAM p.Gln5Ter Pathogenic/Likely pathogenic ★★ same type
EPCAM p.Gln89Ter Pathogenic ★★ same type

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/epcam-p-pro84ser (accessed [today's date]).

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