Is EFS p.Ala186Val (c.557C>T) pathogenic?

EFS p.Ala186Val (c.557C>T) is classified Uncertain significance in EFS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: likely benign (0.0864); Very rare (popmax 0.00972%, amr).

How common is EFS p.Ala186Val (c.557C>T) in the general population?

EFS p.Ala186Val (c.557C>T) is very rare (popmax 0.00972%, amr) (gnomAD).

What do computational predictors say about EFS p.Ala186Val (c.557C>T)?

AlphaMissense predicts likely benign (score 0.0864) — an in-silico prediction, not a clinical call.

EFS p.Ala186Val

c.557C>T · rs763180823 · VCV2384451

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0864 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00972%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0864	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -7.09	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 10	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 7,796 bp · p 0.65 · regional, not allelic
Overall
CADD	18.33	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 0.00972% Admixed American · 5/51,454 alleles

Filtering AF 0.00379% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00246%

Overall 0.00187% 29/1,550,670 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00972%	10,291
African / African-American	0.00274%	36,441
European (non-Finnish)	0.00191%	52,250

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: EFS
Protein: p.Ala186Val
Coding: c.557C>T
MANE Select: NM_005864
dbSNP: rs763180823
Type: single nucleotide variant
Location: chr14:23359921 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.71
Residue 186: the 'disordered' region

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

Similar variants

EFS p.Pro141= Benign ★★ same type
EFS p.Ala167Thr Uncertain significance ★ ⚠ same type
EFS p.Ala219Asp Uncertain significance ★ ⚠ same type
EFS p.Ala262Ser Uncertain significance ★ ⚠ same type
EFS p.Ala285Ser Uncertain significance ★ ⚠ same type
EFS p.Ala40Val Uncertain significance ★ ⚠ same type
EFS p.Ala495Pro Uncertain significance ★ ⚠ same type
EFS p.Ala498Val 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/efs-p-ala186val (accessed [today's date]).

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