Is IFT74 p.Ala558Val (c.1673C>T) pathogenic?

IFT74 p.Ala558Val (c.1673C>T) is classified Uncertain significance in IFT74 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-29). AlphaMissense: likely benign (0.0632); Ultra-rare (popmax 0.0202%, afr).

How common is IFT74 p.Ala558Val (c.1673C>T) in the general population?

IFT74 p.Ala558Val (c.1673C>T) is ultra-rare (popmax 0.0202%, afr) (gnomAD).

What do computational predictors say about IFT74 p.Ala558Val (c.1673C>T)?

AlphaMissense predicts likely benign (score 0.0632) — an in-silico prediction, not a clinical call.

IFT74 p.Ala558Val

c.1673C>T · rs199562248 · VCV2044825

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0632 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0202%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0632	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -5.89	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 4.2	GERP 0.33, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 101 kb · p 1.9e-05 · regional, not allelic
Overall
CADD	17.67	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 0.0202% African / African-American · 15/74,178 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00998%

Overall 0.00407% 65/1,596,716 alleles · ultra-rare exomes 54/1,445,022 · genomes 11/151,694 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0202%	4,945
Middle Eastern	0.0166%	6,010
European (non-Finnish)	0.00376%	26,575
East Asian	0.00226%	44,256
South Asian	0.00225%	44,542
Admixed American	0.0017%	58,796
Remaining individualsnot grpmax-eligible	0.00162%	61,636

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: IFT74
Protein: p.Ala558Val
Coding: c.1673C>T
MANE Select: NM_025103
dbSNP: rs199562248
Type: single nucleotide variant
Location: chr9:27060640 (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

Similar variants

IFT74 p.Ala558Pro Uncertain significance ★ ⚠ same residue
IFT74 p.Ala558= Likely benign ★ same residue
IFT74 c.1685-1G>T Pathogenic/Likely pathogenic ★★ same type
IFT74 p.Gln179Glu Pathogenic/Likely pathogenic ★★ ⚠ same type
IFT74 p.Glu120Ter Pathogenic/Likely pathogenic ★★ same type
IFT74 p.Glu285Ter Pathogenic/Likely pathogenic ★★ same type
IFT74 p.Ala196Val Uncertain significance ★★ ⚠ same type
IFT74 p.Arg182Gln Uncertain significance ★★ ⚠ 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/ift74-p-ala558val (accessed [today's date]).

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