Is EPCAM p.Pro84Arg (c.251C>G) pathogenic?

EPCAM p.Pro84Arg (c.251C>G) is classified Uncertain significance in EPCAM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-08). AlphaMissense: likely pathogenic (0.73); Very rare (popmax 0.000339%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with EPCAM p.Pro84Arg (c.251C>G)?

EPCAM p.Pro84Arg (c.251C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is EPCAM p.Pro84Arg (c.251C>G) in the general population?

EPCAM p.Pro84Arg (c.251C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about EPCAM p.Pro84Arg (c.251C>G)?

AlphaMissense predicts likely pathogenic (score 0.73) — an in-silico prediction, not a clinical call.

EPCAM p.Pro84Arg

c.251C>G · VCV3275851

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.73 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.73	likely pathogenic
REVEL	0.527	indeterminate
SaProt	LLR -4.01	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 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 1.32	unconstrained · MANE · 17 kb · p 4.4e-10 · regional, not allelic
Overall
CADD	25.0	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 0.000339% European (non-Finnish) · 4/1,180,030 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,888 alleles · very rare

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.Pro84Arg
Coding: c.251C>G
MANE Select: NM_002354
Type: single nucleotide variant
Location: chr2:47373874 (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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPCAM p.Pro84Ser Uncertain significance ★ ⚠ same residue
EPCAM c.491+1G>A Pathogenic ★★ same condition
EPCAM p.Ala22Thr Uncertain significance ★★ ⚠ same condition
EPCAM p.Ala256Ser Uncertain significance ★★ ⚠ same condition
EPCAM p.Ala278Val Uncertain significance ★★ same condition
EPCAM p.Ala87Val Uncertain significance ★★ same condition
EPCAM p.Arg173Cys Uncertain significance ★★ ⚠ same condition
EPCAM p.Arg293Lys Uncertain significance ★★ ⚠ 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/epcam-p-pro84arg (accessed [today's date]).

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