Is IFT74 p.Ala558Pro (c.1672G>C) pathogenic?

IFT74 p.Ala558Pro (c.1672G>C) is classified Uncertain significance in IFT74 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). AlphaMissense: likely pathogenic (0.6934); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with IFT74 p.Ala558Pro (c.1672G>C)?

IFT74 p.Ala558Pro (c.1672G>C) is associated with Inborn genetic diseases (ClinVar).

How common is IFT74 p.Ala558Pro (c.1672G>C) in the general population?

IFT74 p.Ala558Pro (c.1672G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IFT74 p.Ala558Pro (c.1672G>C)?

AlphaMissense predicts likely pathogenic (score 0.6934) — an in-silico prediction, not a clinical call.

IFT74 p.Ala558Pro

c.1672G>C · VCV4621980

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6934 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6934	likely pathogenic · top 8% in IFT74
REVEL	0.05	moderately benign-leaning
SaProt	LLR -11.68	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 101 kb · p 1.9e-05 · regional, not allelic
Overall
CADD	24.4	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

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: IFT74
Protein: p.Ala558Pro
Coding: c.1672G>C
MANE Select: NM_025103
Type: single nucleotide variant
Location: chr9:27060639 (GRCh38)
Gene constraint: LOEUF 1.508 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.21
Residue 558: a UniProt-annotated variant site (in jbts40)

Full IFT74 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

IFT74 p.Ala558Val Uncertain significance ★★ ⚠ same residue
IFT74 p.Ala558= Likely benign ★ same residue
IFT74 p.Gln179Glu Pathogenic/Likely pathogenic ★★ ⚠ same condition
IFT74 p.Arg182Gln Uncertain significance ★★ ⚠ same condition
IFT74 p.Arg402Gly Uncertain significance ★★ ⚠ same condition
IFT74 p.Arg406His Uncertain significance ★★ ⚠ same condition
IFT74 p.Arg448Cys Uncertain significance ★★ ⚠ same condition
IFT74 p.Arg51Cys 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/ift74-p-ala558pro (accessed [today's date]).

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