Is EPCAM p.Ser136Pro (c.406T>C) pathogenic?

EPCAM p.Ser136Pro (c.406T>C) is classified Uncertain significance in EPCAM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-12). AlphaMissense: likely benign (0.1103); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with EPCAM p.Ser136Pro (c.406T>C)?

EPCAM p.Ser136Pro (c.406T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is EPCAM p.Ser136Pro (c.406T>C) in the general population?

EPCAM p.Ser136Pro (c.406T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPCAM p.Ser136Pro (c.406T>C)?

AlphaMissense predicts likely benign (score 0.1103) — an in-silico prediction, not a clinical call.

EPCAM p.Ser136Pro

c.406T>C · VCV4640469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1103 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1103	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -4.88	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 0.28	GERP -5.1, phastCons 0.64
Regional constraint	o/e 1.32	unconstrained · MANE · 17 kb · p 4.4e-10 · regional, not allelic
Overall
CADD	18.76	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EPCAM
Protein: p.Ser136Pro
Coding: c.406T>C
MANE Select: NM_002354
Type: single nucleotide variant
Location: chr2:47374029 (GRCh38)
Gene constraint: LOEUF 1.341 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.71 · 2 PDB
Residue 136: a UniProt-annotated variant site (in diar5; likely pathogenic)

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.Ser136Cys 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-ser136pro (accessed [today's date]).

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