Is IFT74 p.Arg23Ser (c.69G>C) pathogenic?

IFT74 p.Arg23Ser (c.69G>C) is classified Uncertain significance in IFT74 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-28). AlphaMissense: likely pathogenic (0.7668); Very rare (popmax 0.00439%, sas).

How common is IFT74 p.Arg23Ser (c.69G>C) in the general population?

IFT74 p.Arg23Ser (c.69G>C) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about IFT74 p.Arg23Ser (c.69G>C)?

AlphaMissense predicts likely pathogenic (score 0.7668) — an in-silico prediction, not a clinical call.

IFT74 p.Arg23Ser

c.69G>C · rs775728464 · VCV2104435

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7668 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7668	likely pathogenic · top 6% in IFT74
REVEL	0.168	moderately benign-leaning
SaProt	LLR -8.32	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.79	GERP -2.1, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 101 kb · p 1.9e-05 · regional, not allelic
Overall
CADD	19.17	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 0.00439% South Asian · 4/91,080 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000372% 6/1,614,012 alleles · very rare exomes 5/1,461,846 · genomes 1/152,166 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,770
European (non-Finnish)	0.000169%	589,998

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.Arg23Ser
Coding: c.69G>C
MANE Select: NM_025103
dbSNP: rs775728464
Type: single nucleotide variant
Location: chr9:26962036 (GRCh38)
Gene constraint: LOEUF 1.508 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.21
Residue 23: the 'basic region' region; the 'disordered' region

Full IFT74 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IFT74 p.Arg23fs Pathogenic ★ 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.Ala558Val 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-arg23ser (accessed [today's date]).

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