Is CYB5RL p.Pro20Ser (c.58C>T) pathogenic?

CYB5RL p.Pro20Ser (c.58C>T) is classified Uncertain significance in CYB5RL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely pathogenic (0.7509); Absent from gnomAD v4.1.

How common is CYB5RL p.Pro20Ser (c.58C>T) in the general population?

CYB5RL p.Pro20Ser (c.58C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYB5RL p.Pro20Ser (c.58C>T)?

AlphaMissense predicts likely pathogenic (score 0.7509) — an in-silico prediction, not a clinical call.

CYB5RL p.Pro20Ser

c.58C>T · VCV4236595

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7509 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7509	likely pathogenic · top 8% in CYB5RL
REVEL	0.479	indeterminate
SaProt	LLR -14.69	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 21 kb · p 0.75 · regional, not allelic
Overall
CADD	23.8	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

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: CYB5RL
Protein: p.Pro20Ser
Coding: c.58C>T
MANE Select: NM_001031672
Type: single nucleotide variant
Location: chr1:54195559 (GRCh38)
Gene constraint: LOEUF 1.327 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.33
Residue 20: the oxidoreductase-like domain

Full CYB5RL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYB5RL p.Pro20Leu Uncertain significance ★ same residue
CYB5RL p.Ala127Thr Uncertain significance ★ ⚠ same type
CYB5RL p.Ala14Gly Uncertain significance ★ ⚠ same type
CYB5RL p.Ala292Val Uncertain significance ★ ⚠ same type
CYB5RL p.Ala305Ser Uncertain significance ★ ⚠ same type
CYB5RL p.Arg108Trp Uncertain significance ★ ⚠ same type
CYB5RL p.Arg154Pro Uncertain significance ★ ⚠ same type
CYB5RL p.Arg241Gly 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/cyb5rl-p-pro20ser (accessed [today's date]).

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