Is CYB5RL p.Ser34Pro (c.100T>C) pathogenic?

CYB5RL p.Ser34Pro (c.100T>C) is classified Uncertain significance in CYB5RL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-08). AlphaMissense: likely benign (0.2641); Absent from gnomAD v4.1.

How common is CYB5RL p.Ser34Pro (c.100T>C) in the general population?

CYB5RL p.Ser34Pro (c.100T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYB5RL p.Ser34Pro (c.100T>C)?

AlphaMissense predicts likely benign (score 0.2641) — an in-silico prediction, not a clinical call.

CYB5RL p.Ser34Pro

c.100T>C · VCV3270466

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2641 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2641	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -12.83	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.95, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 21 kb · p 0.75 · regional, not allelic
Overall
CADD	21.4	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: CYB5RL
Protein: p.Ser34Pro
Coding: c.100T>C
MANE Select: NM_001031672
Type: single nucleotide variant
Location: chr1:54195517 (GRCh38)
Gene constraint: LOEUF 1.327 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.33
Residue 34: the oxidoreductase-like domain

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

Similar variants

CYB5RL p.Ser34Leu 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-ser34pro (accessed [today's date]).

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