Is LITAF p.Ile92Val (c.274A>G) pathogenic?

LITAF p.Ile92Val (c.274A>G) is classified Benign in LITAF (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0588); Common (popmax 22.1%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Charcot-Marie-Tooth disease.

What condition is associated with LITAF p.Ile92Val (c.274A>G)?

LITAF p.Ile92Val (c.274A>G) is associated with Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 1C (ClinVar).

What do computational predictors say about LITAF p.Ile92Val (c.274A>G)?

AlphaMissense predicts likely benign (score 0.0588) — an in-silico prediction, not a clinical call.

LITAF p.Ile92Val

Q: How common is LITAF p.Ile92Val (c.274A>G) in the general population?

LITAF p.Ile92Val (c.274A>G) is common (popmax 22.1%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.274A>G · rs4280262 · VCV317782

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0588 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 22.1%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
AlphaMissense	0.0588	likely benign
REVEL	0.202	benign-leaning
SaProt	LLR -5.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.79	GERP -2.9
Regional constraint	o/e 0.97	unconstrained · MANE · 7,090 bp · p 0.61 · regional, not allelic
Overall
CADD	0.082	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 22.1% European (non-Finnish) · 260,712/1,179,874 alleles

Filtering AF 22% ClinGen BA1/BS1 input FAF95, joint · FAF99 22%

Overall 19.6% 316,180/1,613,820 alleles · common exomes 292,273/1,461,742 · genomes 23,907/152,078 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	22.1%	5
Finnishnot grpmax-eligible	20.9%	5
Amishnot grpmax-eligible	19.2%	5
Remaining individualsnot grpmax-eligible	17.5%	6
Ashkenazi Jewishnot grpmax-eligible	15.8%	6
Admixed American	13.8%	7
Middle Eastern	12.3%	8
South Asian	10.4%	10
East Asian	6.74%	15
African / African-American	6.35%	16

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.Ile92Val
Coding: c.274A>G
MANE Select: NM_001136472
dbSNP: rs4280262
Type: single nucleotide variant
Location: chr16:11553636 (GRCh38)
Gene constraint: LOEUF 1.017 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 70.60
Residue 92: the litaf domain; a UniProt-annotated variant site (in)

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.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
LITAF p.Ala153Thr Uncertain significance ★★ ⚠ same condition
LITAF p.Ala153Val 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-ile92val (accessed [today's date]).

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