Is LITAF p.Pro135Ser (c.403C>T) pathogenic?

LITAF p.Pro135Ser (c.403C>T) is classified Uncertain significance in LITAF (ClinVar, No assertion criteria, 2 submitters). AlphaMissense: likely pathogenic (0.9912); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease.

What condition is associated with LITAF p.Pro135Ser (c.403C>T)?

LITAF p.Pro135Ser (c.403C>T) is associated with Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 1C (ClinVar).

How common is LITAF p.Pro135Ser (c.403C>T) in the general population?

LITAF p.Pro135Ser (c.403C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LITAF p.Pro135Ser (c.403C>T)?

AlphaMissense predicts likely pathogenic (score 0.9912) — an in-silico prediction, not a clinical call.

LITAF p.Pro135Ser

c.403C>T · rs281865135 · VCV41231

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9912 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
AlphaMissense	0.9912	likely pathogenic · top 4% in LITAF
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -13.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,090 bp · p 0.61 · regional, not allelic
Overall
CADD	29.2	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

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: LITAF
Protein: p.Pro135Ser
Coding: c.403C>T
MANE Select: NM_001136472
dbSNP: rs281865135
Type: single nucleotide variant
Location: chr16:11549720 (GRCh38)
Gene constraint: LOEUF 1.017 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 70.60
Residue 135: the litaf domain

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

Disease context

Charcot-Marie-Tooth disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

LITAF p.Pro135Ala Likely pathogenic ★ same residue
LITAF p.Pro135Thr Pathogenic ★ same residue
LITAF p.Pro135Leu Uncertain significance ★ ⚠ same residue
LITAF p.Pro135Arg Uncertain significance ⚠ 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

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-pro135ser (accessed [today's date]).

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