Is RHBDF2 p.Phe381Val (c.1141T>G) pathogenic?

RHBDF2 p.Phe381Val (c.1141T>G) is classified Uncertain significance in RHBDF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-16). AlphaMissense: likely benign (0.0953); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with RHBDF2 p.Phe381Val (c.1141T>G)?

RHBDF2 p.Phe381Val (c.1141T>G) is associated with Inborn genetic diseases (ClinVar).

How common is RHBDF2 p.Phe381Val (c.1141T>G) in the general population?

RHBDF2 p.Phe381Val (c.1141T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about RHBDF2 p.Phe381Val (c.1141T>G)?

AlphaMissense predicts likely benign (score 0.0953) — an in-silico prediction, not a clinical call.

RHBDF2 p.Phe381Val

c.1141T>G · rs2073728505 · VCV2604255

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0953 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0953	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -6.32	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 8.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 7,466 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	23.4	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F410V vs ClinVar F381V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,946 alleles

Overall 6.26e-05% 1/1,597,832 alleles · very rare exomes 1/1,445,526 · genomes 0/152,306 · joint denominator

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: RHBDF2
Protein: p.Phe381Val
Coding: c.1141T>G
MANE Select: NM_001005498
dbSNP: rs2073728505
Type: single nucleotide variant
Location: chr17:76475116 (GRCh38)
Gene constraint: LOEUF 0.545 · pLI 0.15 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.53 · 5 PDB
Residue 410 UniProt numbering: an α-helix

Full RHBDF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RHBDF2 p.Phe381= Likely benign ★ same residue
RHBDF2 p.Ala700Thr Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Arg205His Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Arg206Cys Uncertain significance ★★ same condition
RHBDF2 p.Arg226Cys Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Arg235Trp Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Arg312Gln Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Arg351Cys Uncertain significance ★★ ⚠ same condition

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/rhbdf2-p-phe381val (accessed [today's date]).

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