Is EFCAB3 p.Arg25Ser (c.75G>T) pathogenic?

EFCAB3 p.Arg25Ser (c.75G>T) is classified Uncertain significance in EFCAB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-05). AlphaMissense: ambiguous (0.3576); Very rare (popmax 8.5e-05%, nfe).

How common is EFCAB3 p.Arg25Ser (c.75G>T) in the general population?

EFCAB3 p.Arg25Ser (c.75G>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about EFCAB3 p.Arg25Ser (c.75G>T)?

AlphaMissense predicts ambiguous (score 0.3576) — an in-silico prediction, not a clinical call.

EFCAB3 p.Arg25Ser

c.75G>T · VCV3843575

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3576 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3576	ambiguous
REVEL	0.203	benign-leaning
SaProt	LLR -5.53	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.37	acceptor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.9	GERP -0.62, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 33 kb · p 0.00011 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.5e-05% European (non-Finnish) · 1/1,176,262 alleles

Overall 6.87e-05% 1/1,455,742 alleles · very 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: EFCAB3
Protein: p.Arg25Ser
Coding: c.75G>T
MANE Select: NM_173503
Type: single nucleotide variant
Location: chr17:62387340 (GRCh38)
Gene constraint: LOEUF 1.102 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.80

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-arg25ser (accessed [today's date]).

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