Is CLYBL p.Arg259Ter (c.775C>T) pathogenic?

CLYBL p.Arg259Ter (c.775C>T) is classified Likely benign in CLYBL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-31). Low-frequency (popmax 4.48%, eas).

How common is CLYBL p.Arg259Ter (c.775C>T) in the general population?

CLYBL p.Arg259Ter (c.775C>T) is low-frequency (popmax 4.48%, eas) (gnomAD).

CLYBL p.Arg259Ter

c.775C>T · VCV3907742

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

low-frequency (popmax 4.48%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 9
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -3.4, phastCons 0.26
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.48% East Asian · 2,013/44,884 alleles

Filtering AF 4.32% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.26%

Overall 2.64% 42,670/1,613,646 alleles · low-frequency

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	4.7%	21
East Asiangrpmax	4.48%	22
Finnishnot grpmax-eligible	3.52%	28
Middle Eastern	3.45%	29
Admixed American	3.03%	33
Remaining individualsnot grpmax-eligible	2.82%	35
European (non-Finnish)	2.6%	38
South Asian	2.39%	42
African / African-American	0.519%	193
Amishnot grpmax-eligible	0.11%	912

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg259Ter
Coding: c.775C>T
MANE Select: NM_206808
Type: single nucleotide variant
Location: chr13:99866380 (GRCh38)
Gene constraint: LOEUF 1.186 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.00 · 3 PDB
Residue 259: a UniProt-annotated variant site (loss of the protein product; reduction of circulating vitamin b12); an α-helix

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

Similar variants

CLYBL p.Arg259Gln Uncertain significance ★ ⚠ same residue
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

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-arg259ter (accessed [today's date]).

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