Is EFCAB5 p.Arg561Ser (c.1683G>T) pathogenic?

EFCAB5 p.Arg561Ser (c.1683G>T) is classified Benign in EFCAB5 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-02-14). AlphaMissense: likely benign (0.1024); Common (popmax 28.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with EFCAB5-related disorder.

What condition is associated with EFCAB5 p.Arg561Ser (c.1683G>T)?

EFCAB5 p.Arg561Ser (c.1683G>T) is associated with EFCAB5-related disorder (ClinVar).

What do computational predictors say about EFCAB5 p.Arg561Ser (c.1683G>T)?

AlphaMissense predicts likely benign (score 0.1024) — an in-silico prediction, not a clinical call.

EFCAB5 p.Arg561Ser

Q: How common is EFCAB5 p.Arg561Ser (c.1683G>T) in the general population?

EFCAB5 p.Arg561Ser (c.1683G>T) is common (popmax 28.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1683G>T · rs9900546 · VCV3056518

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1024 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 28.1%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EFCAB5-related disorder

Computational evidence

Protein change
AlphaMissense	0.1024	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -7.44	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 -2.7	GERP -1.4
Regional constraint	o/e 0.95	unconstrained · MANE · 166 kb · p 0.049 · regional, not allelic
Overall
CADD	0.362	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 28.1% African / African-American · 21,088/74,930 alleles

Filtering AF 27.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 27.7%

Overall 4.07% 65,680/1,613,742 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	28.1%	4
Middle Eastern	8.53%	12
Remaining individualsnot grpmax-eligible	4.78%	21
Admixed American	3.7%	27
European (non-Finnish)	2.99%	33
Ashkenazi Jewishnot grpmax-eligible	2.93%	34
South Asian	2.07%	48
Finnishnot grpmax-eligible	1.23%	81
Amishnot grpmax-eligible	0.33%	303
East Asian	0.0847%	1,181

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.Arg561Ser
Coding: c.1683G>T
MANE Select: NM_198529
dbSNP: rs9900546
Type: single nucleotide variant
Location: chr17:30053637 (GRCh38)
Gene constraint: LOEUF 0.908 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.22
Residue 561: a UniProt-annotated variant site (in); the 'disordered' region

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

Disease context

EFCAB5-related disorder

Similar variants

EFCAB5 c.2365+5A>G Likely benign same condition
EFCAB5 c.2738-5079G>A Likely benign same condition
EFCAB5 c.3198-8T>C Likely benign same condition
EFCAB5 p.Ala1120Ser Likely benign same condition
EFCAB5 p.Cys800Phe Benign same condition
EFCAB5 p.Gln481Glu Benign same condition
EFCAB5 p.Glu64Gly Likely benign same condition
EFCAB5 p.Gly1101= Benign 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/efcab5-p-arg561ser (accessed [today's date]).

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