Is IFT54 p.Ser405= (c.1215T>C) pathogenic?

IFT54 p.Ser405= (c.1215T>C) is classified Benign/Likely benign in IFT54 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-12). Ultra-rare (popmax 0.015%, amr).

How common is IFT54 p.Ser405= (c.1215T>C) in the general population?

IFT54 p.Ser405= (c.1215T>C) is ultra-rare (popmax 0.015%, amr) (gnomAD).

IFT54 p.Ser405=

c.1215T>C · rs139991626 · VCV1165570

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2	GERP -2.4
Overall
CADD	1.229	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/60,004 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00684%

Overall 0.0396% 639/1,614,116 alleles · ultra-rare exomes 573/1,461,882 · genomes 66/152,234 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.52%	66
Remaining individualsnot grpmax-eligible	0.115%	868
Admixed Americangrpmax	0.015%	6,667
European (non-Finnish)	0.00873%	11,457
African / African-American	0.00267%	37,475
East Asian	0.00223%	44,902
South Asian	0.0022%	45,543

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser405=
Coding: c.1215T>C
MANE Select: NM_015650
dbSNP: rs139991626
Type: single nucleotide variant
Location: chr2:238344552 (GRCh38)
Structure: AlphaFold pLDDT 61.95 · 2 PDB
Residue 405: the 'disordered' region; the 'disc1-interaction domain' region

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

Similar variants

TRAF3IP1 p.Ser405Gly Uncertain significance ★ ⚠ 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-ser405 (accessed [today's date]).

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