Is CYB5R3 p.Pro44Ser (c.130C>T) pathogenic?

CYB5R3 p.Pro44Ser (c.130C>T) is classified Uncertain significance in CYB5R3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-06). AlphaMissense: likely benign (0.1078); Very rare (popmax 0.00133%, afr); Associated with methemoglobinemia due to deficiency of methemoglobin reductase.

What condition is associated with CYB5R3 p.Pro44Ser (c.130C>T)?

CYB5R3 p.Pro44Ser (c.130C>T) is associated with methemoglobinemia due to deficiency of methemoglobin reductase (ClinVar).

How common is CYB5R3 p.Pro44Ser (c.130C>T) in the general population?

CYB5R3 p.Pro44Ser (c.130C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Autosomal recessive methemoglobinemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CYB5R3 p.Pro44Ser (c.130C>T)?

AlphaMissense predicts likely benign (score 0.1078) — an in-silico prediction, not a clinical call.

CYB5R3 p.Pro44Ser

c.130C>T · rs778446022 · VCV2440658

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1078 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methemoglobinemia due to deficiency of methemoglobin reductase

Computational evidence

Protein change
AlphaMissense	0.1078	likely benign
REVEL	0.218	benign-leaning
SaProt	LLR -9.18	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 6.4	GERP -0.42, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 30 kb · p 0.0013 · regional, not allelic
Overall
CADD	19.68	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,944 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,613,056 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,944
European (non-Finnish)	0.000424%	235,992

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: CYB5R3
Protein: p.Pro44Ser
Coding: c.130C>T
MANE Select: NM_000398
dbSNP: rs778446022
Type: single nucleotide variant
Location: chr22:42636738 (GRCh38)
Gene constraint: LOEUF 1.074 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.90 · 5 PDB
Residue 44: the fad-binding fr-type domain; a β-strand

Full CYB5R3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

methemoglobinemia due to deficiency of methemoglobin reductase — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive methemoglobinemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

CYB5R3 p.Pro44= Benign ★★ same residue
CYB5R3 p.Pro44Leu Uncertain significance ★ ⚠ same residue
CYB5R3 c.226+2T>C Pathogenic/Likely pathogenic ★★ same condition
CYB5R3 c.464-2A>C Pathogenic/Likely pathogenic ★★ same condition
CYB5R3 c.547+1G>A Likely pathogenic ★★ same condition
CYB5R3 p.Arg160Ter Pathogenic ★★ same condition
CYB5R3 p.Arg192Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
CYB5R3 p.Arg58Pro Pathogenic ★★ 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/cyb5r3-p-pro44ser (accessed [today's date]).

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