Is CYB5D2 p.Pro75Leu (c.224C>T) pathogenic?

CYB5D2 p.Pro75Leu (c.224C>T) is classified Uncertain significance in CYB5D2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.1439); Absent from gnomAD v4.1.

How common is CYB5D2 p.Pro75Leu (c.224C>T) in the general population?

CYB5D2 p.Pro75Leu (c.224C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYB5D2 p.Pro75Leu (c.224C>T)?

AlphaMissense predicts likely benign (score 0.1439) — an in-silico prediction, not a clinical call.

CYB5D2 p.Pro75Leu

c.224C>T · VCV4836714

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1439 · 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	0.1439	likely benign
REVEL	0.559	indeterminate
SaProt	LLR -10.76	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.4 · regional, not allelic
Overall
CADD	28.9	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: CYB5D2
Protein: p.Pro75Leu
Coding: c.224C>T
MANE Select: NM_144611
Type: single nucleotide variant
Location: chr17:4143979 (GRCh38)
Gene constraint: LOEUF 1.337 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.81
Residue 75: 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-pro75leu (accessed [today's date]).

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