Is CYB5D1 p.Phe73Ser (c.218T>C) pathogenic?

CYB5D1 p.Phe73Ser (c.218T>C) is classified Uncertain significance in CYB5D1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-09). AlphaMissense: likely pathogenic (0.9713); Ultra-rare (popmax 0.036%, afr).

How common is CYB5D1 p.Phe73Ser (c.218T>C) in the general population?

CYB5D1 p.Phe73Ser (c.218T>C) is ultra-rare (popmax 0.036%, afr) (gnomAD).

What do computational predictors say about CYB5D1 p.Phe73Ser (c.218T>C)?

AlphaMissense predicts likely pathogenic (score 0.9713) — an in-silico prediction, not a clinical call.

CYB5D1 p.Phe73Ser

c.218T>C · VCV3498907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9713 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9713	likely pathogenic · top 1% in CYB5D1
REVEL	0.89	moderately pathogenic-leaning
SaProt	LLR -15.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,474 bp · p 0.065 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.036% African / African-American · 27/74,956 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00173% 28/1,614,100 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,776
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: CYB5D1
Protein: p.Phe73Ser
Coding: c.218T>C
MANE Select: NM_144607
Type: single nucleotide variant
Location: chr17:7858460 (GRCh38)
Gene constraint: LOEUF 1.58 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.02 · 1 PDB
Residue 73: the cytochrome b5 heme-binding domain

Full CYB5D1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYB5D1 p.Ala174Thr Uncertain significance ★ ⚠ same type
CYB5D1 p.Ala23Val Uncertain significance ★ ⚠ same type
CYB5D1 p.Arg130Trp Uncertain significance ★ ⚠ same type
CYB5D1 p.Arg136Gln Uncertain significance ★ ⚠ same type
CYB5D1 p.Arg139Gly Uncertain significance ★ ⚠ same type
CYB5D1 p.Arg165Cys Uncertain significance ★ ⚠ same type
CYB5D1 p.Arg18Cys Uncertain significance ★ ⚠ same type
CYB5D1 p.Arg18His 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/cyb5d1-p-phe73ser (accessed [today's date]).

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