Is IFT81 p.Arg554His (c.1661G>A) pathogenic?

IFT81 p.Arg554His (c.1661G>A) is classified Uncertain significance in IFT81 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-10). AlphaMissense: likely benign (0.1119); Very rare (popmax 0.00522%, amr).

How common is IFT81 p.Arg554His (c.1661G>A) in the general population?

IFT81 p.Arg554His (c.1661G>A) is very rare (popmax 0.00522%, amr) (gnomAD).

What do computational predictors say about IFT81 p.Arg554His (c.1661G>A)?

AlphaMissense predicts likely benign (score 0.1119) — an in-silico prediction, not a clinical call.

IFT81 p.Arg554His

c.1661G>A · rs774113612 · VCV1026617

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1119 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00522%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1119	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -8.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 91 kb · p 0.022 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00522% Admixed American · 3/57,436 alleles

Filtering AF 0.00139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000684%

Overall 0.000562% 9/1,601,598 alleles · very rare exomes 7/1,449,476 · genomes 2/152,122 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00522%	19,145
African / African-American	0.0027%	37,048
East Asian	0.00224%	44,600
South Asian	0.00113%	88,260
European (non-Finnish)	0.00017%	587,803

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.Arg554His
Coding: c.1661G>A
MANE Select: NM_014055
dbSNP: rs774113612
Type: single nucleotide variant
Location: chr12:110205459 (GRCh38)
Gene constraint: LOEUF 1.054 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.45
Residue 554: a UniProt-annotated variant site (in srtd19)

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

Similar variants

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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-arg554his (accessed [today's date]).

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