Is EFCAB5 p.Trp1461Cys (c.4383G>C) pathogenic?

EFCAB5 p.Trp1461Cys (c.4383G>C) is classified Uncertain significance in EFCAB5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-07). AlphaMissense: likely pathogenic (0.8832); Very rare (popmax 0.000424%, nfe).

How common is EFCAB5 p.Trp1461Cys (c.4383G>C) in the general population?

EFCAB5 p.Trp1461Cys (c.4383G>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about EFCAB5 p.Trp1461Cys (c.4383G>C)?

AlphaMissense predicts likely pathogenic (score 0.8832) — an in-silico prediction, not a clinical call.

EFCAB5 p.Trp1461Cys

c.4383G>C · rs370264742 · VCV3087448

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8832 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8832	likely pathogenic · top 3% in EFCAB5
REVEL	0.336	indeterminate
SaProt	LLR -4.02	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 166 kb · p 0.049 · regional, not allelic
Overall
CADD	27.0	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 0.000424% European (non-Finnish) · 5/1,178,008 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00355% 57/1,606,408 alleles · very rare exomes 49/1,454,558 · genomes 8/151,850 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.156%	641
Remaining individualsnot grpmax-eligible	0.00966%	10,348
European (non-Finnish)grpmax	0.000424%	235,602

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: EFCAB5
Protein: p.Trp1461Cys
Coding: c.4383G>C
MANE Select: NM_198529
dbSNP: rs370264742
Type: single nucleotide variant
Location: chr17:30107895 (GRCh38)
Gene constraint: LOEUF 0.908 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.22

Full EFCAB5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFCAB5 p.Ala1262Pro Uncertain significance ★ same type
EFCAB5 p.Ala128Thr Uncertain significance ★ ⚠ same type
EFCAB5 p.Ala1493Val Uncertain significance ★ ⚠ same type
EFCAB5 p.Ala373Val Uncertain significance ★ ⚠ same type
EFCAB5 p.Ala514Thr Uncertain significance ★ ⚠ same type
EFCAB5 p.Ala5Pro Uncertain significance ★ ⚠ same type
EFCAB5 p.Arg1158Gln Uncertain significance ★ ⚠ same type
EFCAB5 p.Arg1329Gln 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/efcab5-p-trp1461cys (accessed [today's date]).

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