Is EFHB p.Phe606Val (c.1816T>G) pathogenic?

EFHB p.Phe606Val (c.1816T>G) is classified Uncertain significance in EFHB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-26). AlphaMissense: ambiguous (0.3451); Ultra-rare (popmax 0.0227%, afr).

How common is EFHB p.Phe606Val (c.1816T>G) in the general population?

EFHB p.Phe606Val (c.1816T>G) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about EFHB p.Phe606Val (c.1816T>G)?

AlphaMissense predicts ambiguous (score 0.3451) — an in-silico prediction, not a clinical call.

EFHB p.Phe606Val

c.1816T>G · VCV3843641

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3451 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Computational evidence

Protein change
AlphaMissense	0.3451	ambiguous
REVEL	0.51	indeterminate
SaProt	LLR -6.13	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 54 kb · p 0.007 · regional, not allelic
Overall
CADD	23.5	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 0.0227% African / African-American · 17/74,790 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00125% 20/1,599,628 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,399
Remaining individualsnot grpmax-eligible	0.00323%	31,003
European (non-Finnish)	8.53e-05%	1,172,354

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.Phe606Val
Coding: c.1816T>G
MANE Select: NM_144715
Type: single nucleotide variant
Location: chr3:19888561 (GRCh38)
Gene constraint: LOEUF 1.244 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.23 · 2 PDB
Residue 606: the ef-hand 2 domain

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

Similar variants

EFHB p.Phe606Cys Uncertain significance ★ ⚠ same residue
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

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-phe606val (accessed [today's date]).

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