Is CLYBL p.Arg226Gln (c.677G>A) pathogenic?

CLYBL p.Arg226Gln (c.677G>A) is classified Uncertain significance in CLYBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-08). AlphaMissense: likely pathogenic (0.6275); Ultra-rare (popmax 0.0165%, mid).

How common is CLYBL p.Arg226Gln (c.677G>A) in the general population?

CLYBL p.Arg226Gln (c.677G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CLYBL p.Arg226Gln (c.677G>A)?

AlphaMissense predicts likely pathogenic (score 0.6275) — an in-silico prediction, not a clinical call.

CLYBL p.Arg226Gln

c.677G>A · VCV3834269

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6275 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6275	likely pathogenic
REVEL	0.607	indeterminate
SaProt	LLR -12.53	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 9.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 285 kb · p 0.27 · regional, not allelic
Overall
CADD	33.0	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 0.0165% Middle Eastern · 1/6,044 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000991% 16/1,613,846 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,044
South Asian	0.00659%	15,176
Remaining individualsnot grpmax-eligible	0.0032%	31,240
East Asian	0.00223%	44,876
European (non-Finnish)	0.000508%	196,669

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: CLYBL
Protein: p.Arg226Gln
Coding: c.677G>A
MANE Select: NM_206808
Type: single nucleotide variant
Location: chr13:99866282 (GRCh38)
Gene constraint: LOEUF 1.186 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.00 · 3 PDB
Residue 226: an α-helix

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

Similar variants

CLYBL p.Ala116Val Uncertain significance ★ ⚠ same type
CLYBL p.Ala13Asp Uncertain significance ★ ⚠ same type
CLYBL p.Ala13Val Uncertain significance ★ ⚠ same type
CLYBL p.Ala16Val Uncertain significance ★ ⚠ same type
CLYBL p.Ala17Ser Uncertain significance ★ ⚠ same type
CLYBL p.Ala17Thr Uncertain significance ★ ⚠ same type
CLYBL p.Ala17Val Uncertain significance ★ ⚠ same type
CLYBL p.Ala213Ser 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/clybl-p-arg226gln (accessed [today's date]).

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