Is CYB5D2 p.Arg136Gln (c.407G>A) pathogenic?

CYB5D2 p.Arg136Gln (c.407G>A) is classified Uncertain significance in CYB5D2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: likely benign (0.1052); Rare (popmax 0.131%, afr).

How common is CYB5D2 p.Arg136Gln (c.407G>A) in the general population?

CYB5D2 p.Arg136Gln (c.407G>A) is rare (popmax 0.131%, afr) (gnomAD).

What do computational predictors say about CYB5D2 p.Arg136Gln (c.407G>A)?

AlphaMissense predicts likely benign (score 0.1052) — an in-silico prediction, not a clinical call.

CYB5D2 p.Arg136Gln

c.407G>A · rs139825193 · VCV2265768

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1052 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.131%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1052	likely benign
REVEL	0.497	indeterminate
SaProt	LLR -11.36	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 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.4 · regional, not allelic
Overall
CADD	21.3	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 0.131% African / African-American · 98/75,052 alleles

Filtering AF 0.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.102%

Overall 0.00713% 115/1,614,010 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.131%	766
Remaining individualsnot grpmax-eligible	0.0048%	20,835
European (non-Finnish)	0.00119%	84,280

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.Arg136Gln
Coding: c.407G>A
MANE Select: NM_144611
dbSNP: rs139825193
Type: single nucleotide variant
Location: chr17:4154689 (GRCh38)
Gene constraint: LOEUF 1.337 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.81

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-arg136gln (accessed [today's date]).

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