Is EFHD1 p.Lys100Arg (c.299A>G) pathogenic?

EFHD1 p.Lys100Arg (c.299A>G) is classified Uncertain significance in EFHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.0624); Ultra-rare (popmax 0.0133%, amr).

How common is EFHD1 p.Lys100Arg (c.299A>G) in the general population?

EFHD1 p.Lys100Arg (c.299A>G) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about EFHD1 p.Lys100Arg (c.299A>G)?

AlphaMissense predicts likely benign (score 0.0624) — an in-silico prediction, not a clinical call.

EFHD1 p.Lys100Arg

c.299A>G · rs201353765 · VCV2367533

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0624 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0624	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -7.21	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 2.2	GERP 0.51, phastCons 0.91
Regional constraint	o/e 0.95	unconstrained · MANE · 48 kb · p 0.33 · regional, not allelic
Overall
CADD	15.27	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 0.0133% Admixed American · 8/59,974 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00973%

Overall 0.00964% 154/1,597,276 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,497
European (non-Finnish)	0.012%	8,364
Remaining individualsnot grpmax-eligible	0.00802%	12,463

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: EFHD1
Protein: p.Lys100Arg
Coding: c.299A>G
MANE Select: NM_025202
dbSNP: rs201353765
Type: single nucleotide variant
Location: chr2:232634003 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.10
Residue 100: the ef-hand 1 domain

Full EFHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFHD1 p.Lys100Thr Uncertain significance ★ ⚠ same residue
EFHD1 p.Ala124Thr Uncertain significance ★ ⚠ same type
EFHD1 p.Ala159Val Uncertain significance ★ ⚠ same type
EFHD1 p.Ala19Asp Uncertain significance ★ ⚠ same type
EFHD1 p.Ala49Pro Uncertain significance ★ ⚠ same type
EFHD1 p.Arg13Trp Uncertain significance ★ ⚠ same type
EFHD1 p.Arg149Gln Uncertain significance ★ ⚠ same type
EFHD1 p.Arg218Trp 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/efhd1-p-lys100arg (accessed [today's date]).

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