Is EPC1 p.Cys185Ser (c.554G>C) pathogenic?

EPC1 p.Cys185Ser (c.554G>C) is classified Uncertain significance in EPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: likely benign (0.1472); Ultra-rare (popmax 0.01%, amr).

How common is EPC1 p.Cys185Ser (c.554G>C) in the general population?

EPC1 p.Cys185Ser (c.554G>C) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about EPC1 p.Cys185Ser (c.554G>C)?

AlphaMissense predicts likely benign (score 0.1472) — an in-silico prediction, not a clinical call.

EPC1 p.Cys185Ser

c.554G>C · VCV3509136

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1472 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1472	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -8.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 13 kb · p 0.0054 · regional, not allelic
Overall
CADD	21.4	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 0.01% Admixed American · 6/59,988 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000411% 6/1,461,012 alleles · ultra-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: EPC1
Protein: p.Cys185Ser
Coding: c.554G>C
MANE Select: NM_001272004
Type: single nucleotide variant
Location: chr10:32293100 (GRCh38)
Gene constraint: LOEUF 0.229 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 57.95 · 9 PDB

Full EPC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPC1 c.1863+114C>T Uncertain significance ★ ⚠ same type
EPC1 c.314-1G>T Uncertain significance ★ same type
EPC1 p.Ala229Thr Uncertain significance ★ ⚠ same type
EPC1 p.Ala604Thr Uncertain significance ★ ⚠ same type
EPC1 p.Ala770Thr Uncertain significance ★ ⚠ same type
EPC1 p.Arg238Gln Uncertain significance ★ ⚠ same type
EPC1 p.Arg336Trp Uncertain significance ★ ⚠ same type
EPC1 p.Arg405His Uncertain significance ★ ⚠ 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/epc1-p-cys185ser (accessed [today's date]).

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