Is OFD1 p.Ala540= (c.1620C>T) pathogenic?

OFD1 p.Ala540= (c.1620C>T) is classified Likely benign in OFD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-20). Very rare (popmax 0.00969%, nfe); Associated with Joubert syndrome.

What condition is associated with OFD1 p.Ala540= (c.1620C>T)?

OFD1 p.Ala540= (c.1620C>T) is associated with Joubert syndrome, orofaciodigital syndrome I (ClinVar).

How common is OFD1 p.Ala540= (c.1620C>T) in the general population?

OFD1 p.Ala540= (c.1620C>T) is very rare (popmax 0.00969%, nfe) (gnomAD).

OFD1 p.Ala540=

c.1620C>T · rs142659184 · VCV1656250

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00969%, nfe)

Conditions

Joubert syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8	GERP -13
Overall
CADD	0.038	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00969% European (non-Finnish) · 86/887,951 alleles

Filtering AF 0.00802% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0074%

Overall 0.00775% 93/1,200,692 alleles · very rare exomes 87/1,089,455 · genomes 6/111,237 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00969%	10,325
African / African-American	0.0088%	11,365
Remaining individualsnot grpmax-eligible	0.00423%	23,627

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: OFD1
Protein: p.Ala540=
Coding: c.1620C>T
MANE Select: NM_003611
dbSNP: rs142659184
Type: single nucleotide variant
Location: chrX:13758414 (GRCh38)
Structure: AlphaFold pLDDT 68.41

Full OFD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Joubert syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: orofaciodigital syndrome I

Similar variants

OFD1 c.1411+1G>A Pathogenic ★★ same condition
OFD1 c.2600-1G>C Pathogenic/Likely pathogenic ★★ same condition
OFD1 p.Arg367Ter Pathogenic ★★ same condition
OFD1 p.Arg41Ter Pathogenic ★★ same condition
OFD1 p.Arg890Ter Pathogenic/Likely pathogenic ★★ same condition
OFD1 p.Arg909Ter Pathogenic/Likely pathogenic ★★ same condition
OFD1 p.Tyr87Cys Pathogenic ★★ ⚠ same condition
OFD1 c.2388-3T>C 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/ofd1-p-ala540 (accessed [today's date]).

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