Is EFHB p.Glu45Lys (c.133G>A) pathogenic?

EFHB p.Glu45Lys (c.133G>A) is classified Uncertain significance in EFHB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-04). AlphaMissense: likely benign (0.0737); Ultra-rare (popmax 0.0267%, afr).

How common is EFHB p.Glu45Lys (c.133G>A) in the general population?

EFHB p.Glu45Lys (c.133G>A) is ultra-rare (popmax 0.0267%, afr) (gnomAD).

What do computational predictors say about EFHB p.Glu45Lys (c.133G>A)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

EFHB p.Glu45Lys

c.133G>A · rs370568834 · VCV2363206

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -7.11	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 0.63	GERP -1.8, phastCons 0.012
Regional constraint	o/e 1.09	unconstrained · MANE · 54 kb · p 0.007 · regional, not allelic
Overall
CADD	14.59	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 0.0267% African / African-American · 20/74,916 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00155% 25/1,613,870 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0267%	3,746
South Asian	0.00329%	30,359
Remaining individualsnot grpmax-eligible	0.0032%	31,227

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: EFHB
Protein: p.Glu45Lys
Coding: c.133G>A
MANE Select: NM_144715
dbSNP: rs370568834
Type: single nucleotide variant
Location: chr3:19933886 (GRCh38)
Gene constraint: LOEUF 1.244 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.23 · 2 PDB

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

Similar variants

EFHB p.Lys557Gln Likely benign ★★ same type
EFHB p.Ala145Ser Uncertain significance ★ ⚠ same type
EFHB p.Ala264Pro Uncertain significance ★ ⚠ same type
EFHB p.Ala291Thr Uncertain significance ★ ⚠ same type
EFHB p.Ala460Ser Uncertain significance ★ ⚠ same type
EFHB p.Ala550Glu Uncertain significance ★ ⚠ same type
EFHB p.Ala623Thr Uncertain significance ★ ⚠ same type
EFHB p.Ala623Val 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/efhb-p-glu45lys (accessed [today's date]).

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