Is EPCAM p.Pro244Ser (c.730C>T) pathogenic?

EPCAM p.Pro244Ser (c.730C>T) is classified Uncertain significance in EPCAM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-29). AlphaMissense: likely benign (0.2029); Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with EPCAM p.Pro244Ser (c.730C>T)?

EPCAM p.Pro244Ser (c.730C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is EPCAM p.Pro244Ser (c.730C>T) in the general population?

EPCAM p.Pro244Ser (c.730C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about EPCAM p.Pro244Ser (c.730C>T)?

AlphaMissense predicts likely benign (score 0.2029) — an in-silico prediction, not a clinical call.

EPCAM p.Pro244Ser

c.730C>T · rs755757555 · VCV2562280

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2029 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2029	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -7.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 2, phastCons 1
Regional constraint	o/e 1.32	unconstrained · MANE · 17 kb · p 4.4e-10 · regional, not allelic
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,988 alleles

Overall 0.000205% 3/1,461,868 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
African / African-Americangrpmax	0.00133%	74,988
European (non-Finnish)	8.47e-05%	1,180,013

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: EPCAM
Protein: p.Pro244Ser
Coding: c.730C>T
MANE Select: NM_002354
dbSNP: rs755757555
Type: single nucleotide variant
Location: chr2:47379841 (GRCh38)
Gene constraint: LOEUF 1.341 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.71 · 2 PDB
Residue 244: a UniProt-annotated variant site (in diar5; likely pathogenic); an α-helix

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.Pro244= Likely benign ★ same residue
EPCAM p.Pro244Ala 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

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-pro244ser (accessed [today's date]).

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