Is IFT81 p.Leu112Pro (c.335T>C) pathogenic?

IFT81 p.Leu112Pro (c.335T>C) is classified Uncertain significance in IFT81 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). AlphaMissense: likely pathogenic (0.9677); Very rare (popmax 0.00345%, amr); Associated with Inborn genetic diseases.

What condition is associated with IFT81 p.Leu112Pro (c.335T>C)?

IFT81 p.Leu112Pro (c.335T>C) is associated with Inborn genetic diseases (ClinVar).

How common is IFT81 p.Leu112Pro (c.335T>C) in the general population?

IFT81 p.Leu112Pro (c.335T>C) is very rare (popmax 0.00345%, amr) (gnomAD).

What do computational predictors say about IFT81 p.Leu112Pro (c.335T>C)?

AlphaMissense predicts likely pathogenic (score 0.9677) — an in-silico prediction, not a clinical call.

IFT81 p.Leu112Pro

c.335T>C · VCV4037567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9677 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00345%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9677	likely pathogenic · top 1% in IFT81
REVEL	0.772	pathogenic-leaning
SaProt	LLR -14.50	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 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 91 kb · p 0.022 · regional, not allelic
Overall
CADD	28.4	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

Grpmax group 0.00345% Admixed American · 2/57,896 alleles

Filtering AF 0.000573% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000214%

Overall 0.000373% 6/1,607,482 alleles · very rare exomes 6/1,455,262 · genomes 0/152,220 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00345%	28,948
European (non-Finnish)	0.000339%	294,571

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: IFT81
Protein: p.Leu112Pro
Coding: c.335T>C
MANE Select: NM_014055
Type: single nucleotide variant
Location: chr12:110129036 (GRCh38)
Gene constraint: LOEUF 1.054 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.45
Residue 112: the 'ch (calponin-homology)-like region' region

Full IFT81 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IFT81 p.Leu112= Likely benign ★ same residue
IFT81 p.Ala116Ser Uncertain significance ★★ ⚠ same condition
IFT81 p.Ala253Thr Uncertain significance ★★ ⚠ same condition
IFT81 p.Ala254Ser Uncertain significance ★★ ⚠ same condition
IFT81 p.Ala357Gly Uncertain significance ★★ ⚠ same condition
IFT81 p.Arg213Gln Uncertain significance ★★ same condition
IFT81 p.Arg251Gly Uncertain significance ★★ ⚠ same condition
IFT81 p.Arg353His 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/ift81-p-leu112pro (accessed [today's date]).

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