Is LITAF p.Arg90Cys (c.268C>T) pathogenic?

LITAF p.Arg90Cys (c.268C>T) is classified Conflicting classifications of pathogenicity in LITAF (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-09-23). AlphaMissense: likely benign (0.305); Ultra-rare (popmax 0.0285%, sas); Associated with hereditary ataxia.

What condition is associated with LITAF p.Arg90Cys (c.268C>T)?

LITAF p.Arg90Cys (c.268C>T) is associated with hereditary ataxia, Charcot-Marie-Tooth disease type 1C, Charcot-Marie-Tooth disease (ClinVar).

How common is LITAF p.Arg90Cys (c.268C>T) in the general population?

LITAF p.Arg90Cys (c.268C>T) is ultra-rare (popmax 0.0285%, sas) (gnomAD).

What do computational predictors say about LITAF p.Arg90Cys (c.268C>T)?

AlphaMissense predicts likely benign (score 0.305) — an in-silico prediction, not a clinical call.

LITAF p.Arg90Cys

c.268C>T · rs375665454 · VCV641266

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.305 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0285%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary ataxia

Computational evidence

Protein change
AlphaMissense	0.305	likely benign
REVEL	0.656	pathogenic-leaning
SaProt	LLR -7.12	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 0.86, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,090 bp · p 0.61 · regional, not allelic
Overall
CADD	27.0	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

Grpmax group 0.0285% South Asian · 26/91,092 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.00688% 111/1,613,942 alleles · ultra-rare exomes 97/1,461,858 · genomes 14/152,084 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0285%	3,504
Admixed American	0.0267%	3,749
Remaining individualsnot grpmax-eligible	0.0064%	15,620
European (non-Finnish)	0.00492%	20,345
Finnishnot grpmax-eligible	0.00469%	21,335
African / African-American	0.00401%	24,959
East Asian	0.00223%	44,888

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: LITAF
Protein: p.Arg90Cys
Coding: c.268C>T
MANE Select: NM_001136472
dbSNP: rs375665454
Type: single nucleotide variant
Location: chr16:11553642 (GRCh38)
Gene constraint: LOEUF 1.017 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 70.60
Residue 90: the litaf domain

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

Disease context

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

Also linked: Charcot-Marie-Tooth disease type 1C Charcot-Marie-Tooth disease

Similar variants

LITAF p.Arg90His Uncertain significance ★★ ⚠ same residue
LITAF p.Arg90= Likely benign ★ same residue
LITAF p.Ala111Gly Pathogenic ★★ same condition
LITAF p.Gly112Ser Pathogenic ★★ ⚠ same condition
LITAF p.Thr115Asn Pathogenic/Likely pathogenic ★★ same condition
LITAF c.220+4C>T Uncertain significance ★★ same condition
LITAF p.Ala129Val Uncertain significance ★★ ⚠ same condition
LITAF p.Ala140Thr Uncertain significance ★★ ⚠ 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/litaf-p-arg90cys (accessed [today's date]).

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