Is EFHB p.Phe606Cys (c.1817T>G) pathogenic?

EFHB p.Phe606Cys (c.1817T>G) is classified Uncertain significance in EFHB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.5836); Absent from gnomAD v4.1.

How common is EFHB p.Phe606Cys (c.1817T>G) in the general population?

EFHB p.Phe606Cys (c.1817T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EFHB p.Phe606Cys (c.1817T>G)?

AlphaMissense predicts likely pathogenic (score 0.5836) — an in-silico prediction, not a clinical call.

EFHB p.Phe606Cys

c.1817T>G · VCV4247074

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5836 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5836	likely pathogenic
REVEL	0.611	indeterminate
SaProt	LLR -8.81	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 54 kb · p 0.007 · regional, not allelic
Overall
CADD	28.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EFHB
Protein: p.Phe606Cys
Coding: c.1817T>G
MANE Select: NM_144715
Type: single nucleotide variant
Location: chr3:19888560 (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.Phe606Val 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-phe606cys (accessed [today's date]).

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