Is IFT54 p.Ser453Phe (c.1358C>T) pathogenic?

IFT54 p.Ser453Phe (c.1358C>T) is classified Likely benign in IFT54 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.1336); Rare (popmax 0.287%, eas).

How common is IFT54 p.Ser453Phe (c.1358C>T) in the general population?

IFT54 p.Ser453Phe (c.1358C>T) is rare (popmax 0.287%, eas) (gnomAD).

What do computational predictors say about IFT54 p.Ser453Phe (c.1358C>T)?

AlphaMissense predicts likely benign (score 0.1336) — an in-silico prediction, not a clinical call.

IFT54 p.Ser453Phe

c.1358C>T · rs146820102 · VCV794052

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1336 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.287%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1336	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -9.37	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 1.3	GERP -0.68, phastCons 0.001
Regional constraint	o/e 0.94	unconstrained · MANE · 77 kb · p 0.082 · regional, not allelic
Overall
CADD	16.73	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 0.287% East Asian · 129/44,874 alleles

Filtering AF 0.247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.232%

Overall 0.0102% 165/1,614,046 alleles · rare exomes 131/1,461,750 · genomes 34/152,296 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.287%	348
Remaining individualsnot grpmax-eligible	0.0176%	5,682
Middle Eastern	0.0165%	6,060
South Asian	0.0165%	6,072
Admixed American	0.00666%	15,006
European (non-Finnish)	0.000424%	235,986

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: IFT54
Protein: p.Ser453Phe
Coding: c.1358C>T
MANE Select: NM_015650
dbSNP: rs146820102
Type: single nucleotide variant
Location: chr2:238348839 (GRCh38)
Structure: AlphaFold pLDDT 61.95 · 2 PDB
Residue 453: the 'disordered' region; the 'disc1-interaction domain' region

Full IFT54 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IFT54 p.Ser453Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
IFT54 c.1159+1G>C Likely pathogenic ★★ same type
IFT54 c.988-1G>A Likely pathogenic ★★ same type
IFT54 c.988-1G>C Likely pathogenic ★★ same type
IFT54 p.Arg565Ter Pathogenic/Likely pathogenic ★★ same type
IFT54 p.Trp572Ter Pathogenic/Likely pathogenic ★★ same type
IFT54 c.1452-5T>G Uncertain significance ★★ same type
IFT54 c.1910+3G>T 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/ift54-p-ser453phe (accessed [today's date]).

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