Is IFT81 p.Pro100Arg (c.299C>G) pathogenic?

IFT81 p.Pro100Arg (c.299C>G) is classified Uncertain significance in IFT81 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-07). AlphaMissense: ambiguous (0.3417); Very rare (popmax 0.00314%, nfe).

How common is IFT81 p.Pro100Arg (c.299C>G) in the general population?

IFT81 p.Pro100Arg (c.299C>G) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about IFT81 p.Pro100Arg (c.299C>G)?

AlphaMissense predicts ambiguous (score 0.3417) — an in-silico prediction, not a clinical call.

IFT81 p.Pro100Arg

c.299C>G · VCV4918399

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3417 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3417	ambiguous
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -11.57	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 91 kb · p 0.022 · regional, not allelic
Overall
CADD	28.9	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 0.00314% European (non-Finnish) · 37/1,179,708 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00236% 38/1,613,048 alleles · very rare exomes 37/1,461,076 · genomes 1/151,972 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00314%	31,884
African / African-American	0.00134%	74,778

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.Pro100Arg
Coding: c.299C>G
MANE Select: NM_014055
Type: single nucleotide variant
Location: chr12:110129000 (GRCh38)
Gene constraint: LOEUF 1.054 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.45
Residue 100: the 'ch (calponin-homology)-like region' region

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

Similar variants

IFT81 c.1717-2A>G Pathogenic/Likely pathogenic ★★ same type
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IFT81 p.Arg213Ter Pathogenic/Likely pathogenic ★★ same type
IFT81 p.Arg399Ter Pathogenic/Likely pathogenic ★★ same type
IFT81 p.Arg481Ter Pathogenic/Likely pathogenic ★★ same type
IFT81 p.Arg512Ter Pathogenic/Likely pathogenic ★★ same type
IFT81 p.Arg64Ter Pathogenic ★★ same type
IFT81 p.Leu122Ter Pathogenic/Likely pathogenic ★★ same type

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-pro100arg (accessed [today's date]).

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