Is CYB5D2 p.Val130Phe (c.388G>T) pathogenic?

CYB5D2 p.Val130Phe (c.388G>T) is classified Uncertain significance in CYB5D2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely benign (0.2572); Ultra-rare (popmax 0.0168%, mid).

How common is CYB5D2 p.Val130Phe (c.388G>T) in the general population?

CYB5D2 p.Val130Phe (c.388G>T) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about CYB5D2 p.Val130Phe (c.388G>T)?

AlphaMissense predicts likely benign (score 0.2572) — an in-silico prediction, not a clinical call.

CYB5D2 p.Val130Phe

c.388G>T · rs1048089677 · VCV2209604

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2572 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2572	likely benign
REVEL	0.734	pathogenic-leaning
SaProt	LLR -13.46	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.66, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.4 · regional, not allelic
Overall
CADD	20.8	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 0.0168% Middle Eastern · 1/5,936 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00103% 15/1,461,676 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,936
South Asian	0.0132%	7,589
African / African-American	0.00133%	75,038
European (non-Finnish)	8.47e-05%	1,180,034

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: CYB5D2
Protein: p.Val130Phe
Coding: c.388G>T
MANE Select: NM_144611
dbSNP: rs1048089677
Type: single nucleotide variant
Location: chr17:4150028 (GRCh38)
Gene constraint: LOEUF 1.337 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.81
Residue 130: the cytochrome b5 heme-binding domain

Full CYB5D2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYB5D2 p.Ala111Asp Uncertain significance ★ ⚠ same type
CYB5D2 p.Ala177Val Uncertain significance ★ ⚠ same type
CYB5D2 p.Ala17Val Uncertain significance ★ ⚠ same type
CYB5D2 p.Ala18Val Uncertain significance ★ ⚠ same type
CYB5D2 p.Ala19Val Uncertain significance ★ ⚠ same type
CYB5D2 p.Ala22Thr Uncertain significance ★ ⚠ same type
CYB5D2 p.Ala248Ser Uncertain significance ★ ⚠ same type
CYB5D2 p.Ala58Val 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/cyb5d2-p-val130phe (accessed [today's date]).

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