Is EFCAB3 p.Ser409Ala (c.1225T>G) pathogenic?

EFCAB3 p.Ser409Ala (c.1225T>G) is classified Uncertain significance in EFCAB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.0879); Absent from gnomAD v4.1.

How common is EFCAB3 p.Ser409Ala (c.1225T>G) in the general population?

EFCAB3 p.Ser409Ala (c.1225T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EFCAB3 p.Ser409Ala (c.1225T>G)?

AlphaMissense predicts likely benign (score 0.0879) — an in-silico prediction, not a clinical call.

EFCAB3 p.Ser409Ala

c.1225T>G · VCV4663205

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0879 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0879	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -8.34	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 0.41	GERP -3.7, phastCons 0.001
Regional constraint	o/e 0.83	unconstrained · MANE · 33 kb · p 0.00011 · regional, not allelic
Overall
CADD	4.886	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: EFCAB3
Protein: p.Ser409Ala
Coding: c.1225T>G
MANE Select: NM_173503
Type: single nucleotide variant
Location: chr17:62416237 (GRCh38)
Gene constraint: LOEUF 1.102 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.80
Residue 409: the 'disordered' region

Full EFCAB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFCAB3 c.34+6G>T Benign ★★ same type
EFCAB3 c.488+2T>C Benign ★★ same type
EFCAB3 p.Arg99Ter Benign/Likely benign ★★ same type
EFCAB3 p.Lys15Asn Benign ★★ same type
EFCAB3 p.Ser370Phe Benign ★★ same type
EFCAB3 c.-5G>A Uncertain significance ★ same type
EFCAB3 c.-8C>G Uncertain significance ★ same type
EFCAB3 p.Ala208Thr 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/efcab3-p-ser409ala (accessed [today's date]).

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