Is TWNK p.Gly26Val (c.77G>T) pathogenic?

TWNK p.Gly26Val (c.77G>T) is classified Uncertain significance in TWNK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-10). AlphaMissense: likely benign (0.1046); Very rare (popmax 0.0084%, nfe); Associated with autosomal recessive cerebellar ataxia.

How common is TWNK p.Gly26Val (c.77G>T) in the general population?

TWNK p.Gly26Val (c.77G>T) is very rare (popmax 0.0084%, nfe) (gnomAD).

What do computational predictors say about TWNK p.Gly26Val (c.77G>T)?

AlphaMissense predicts likely benign (score 0.1046) — an in-silico prediction, not a clinical call.

TWNK p.Gly26Val

Q: What condition is associated with TWNK p.Gly26Val (c.77G>T)?

TWNK p.Gly26Val (c.77G>T) is associated with autosomal recessive cerebellar ataxia, mitochondrial DNA depletion syndrome 7 (hepatocerebral type), sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (ClinVar).

c.77G>T · rs772221026 · VCV298495

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1046 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0084%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal recessive cerebellar ataxia

Computational evidence

Protein change
AlphaMissense	0.1046	likely benign
REVEL	0.479	indeterminate
SaProt	LLR -6.34	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 912 bp · p 0.04 · regional, not allelic
Overall
CADD	19.94	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0084% European (non-Finnish) · 99/1,178,520 alleles

Filtering AF 0.00703% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00652%

Overall 0.00653% 105/1,607,480 alleles · very rare exomes 99/1,455,486 · genomes 6/151,994 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0084%	11,904
Remaining individualsnot grpmax-eligible	0.00643%	15,561
African / African-American	0.00267%	37,400

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: TWNK
Protein: p.Gly26Val
Coding: c.77G>T
MANE Select: NM_021830
dbSNP: rs772221026
Type: single nucleotide variant
Location: chr10:100988287 (GRCh38)
Gene constraint: LOEUF 0.76 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.71 · 2 PDB
Residue 26: the 'contributes to single strand dna binding activity' region

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

Disease context

autosomal recessive cerebellar ataxia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial DNA depletion syndrome 7 (hepatocerebral type)sensory ataxic neuropathy, dysarthria, and ophthalmoparesis progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3

Similar variants

TWNK p.Gly26Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
TWNK p.Gly26Ala Benign ★ same residue
TWNK p.Ala359Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
TWNK p.Arg217Ter Pathogenic/Likely pathogenic ★★ same condition
TWNK p.Arg285Ter Pathogenic/Likely pathogenic ★★ same condition
TWNK p.Arg303Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
TWNK p.Arg323Ter Pathogenic/Likely pathogenic ★★ same condition
TWNK p.Arg334Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition

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/twnk-p-gly26val (accessed [today's date]).

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