Is CYB5D2 p.Ala90Val (c.269C>T) pathogenic?

CYB5D2 p.Ala90Val (c.269C>T) is classified Uncertain significance in CYB5D2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-04). AlphaMissense: ambiguous (0.5483); Very rare (popmax 0.00133%, afr).

How common is CYB5D2 p.Ala90Val (c.269C>T) in the general population?

CYB5D2 p.Ala90Val (c.269C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CYB5D2 p.Ala90Val (c.269C>T)?

AlphaMissense predicts ambiguous (score 0.5483) — an in-silico prediction, not a clinical call.

CYB5D2 p.Ala90Val

c.269C>T · rs997629466 · VCV2321683

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5483 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5483	ambiguous
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -9.09	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.4 · regional, not allelic
Overall
CADD	26.3	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 0.00133% African / African-American · 1/75,056 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000889% 13/1,461,798 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,056
European (non-Finnish)	0.00102%	98,330

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.Ala90Val
Coding: c.269C>T
MANE Select: NM_144611
dbSNP: rs997629466
Type: single nucleotide variant
Location: chr17:4149909 (GRCh38)
Gene constraint: LOEUF 1.337 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.81
Residue 90: 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-ala90val (accessed [today's date]).

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