Is EPCAM p.Pro244Ala (c.730C>G) pathogenic?

EPCAM p.Pro244Ala (c.730C>G) is classified Uncertain significance in EPCAM (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely benign (0.1186); Very rare (popmax 0.00446%, eas); Associated with Lynch syndrome 1.

What condition is associated with EPCAM p.Pro244Ala (c.730C>G)?

EPCAM p.Pro244Ala (c.730C>G) is associated with Lynch syndrome 1 (ClinVar).

How common is EPCAM p.Pro244Ala (c.730C>G) in the general population?

EPCAM p.Pro244Ala (c.730C>G) is very rare (popmax 0.00446%, eas) (gnomAD).

How is Lynch syndrome inherited?

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

What do computational predictors say about EPCAM p.Pro244Ala (c.730C>G)?

AlphaMissense predicts likely benign (score 0.1186) — an in-silico prediction, not a clinical call.

EPCAM p.Pro244Ala

c.730C>G · rs755757555 · VCV873044

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome 1

Computational evidence

Protein change
AlphaMissense	0.1186	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
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	22.9	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 0.00446% East Asian · 2/44,878 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,614,014 alleles · very rare exomes 2/1,461,868 · genomes 0/152,146 · joint denominator

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.Pro244Ala
Coding: c.730C>G
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

Lynch syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

EPCAM p.Pro244Ser Uncertain significance ★ ⚠ same residue
EPCAM p.Pro244= Likely benign ★ same residue
EPCAM p.Ala87Val Uncertain significance ★★ same condition
EPCAM c.859-6A>G Benign ★★ same condition
EPCAM p.Arg153Thr Benign/Likely benign ★★ same condition
EPCAM p.Asn31Lys Likely benign ★★ same condition
EPCAM p.Met115Thr Benign/Likely benign ★★ same condition
EPCAM c.903+5A>G 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-pro244ala (accessed [today's date]).

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