Is OFD1 p.Ser90Ala (c.268T>G) pathogenic?

OFD1 p.Ser90Ala (c.268T>G) is classified Uncertain significance in OFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-11). AlphaMissense: likely benign (0.1886); Very rare (popmax 0.000112%, nfe); Associated with Joubert syndrome.

What condition is associated with OFD1 p.Ser90Ala (c.268T>G)?

OFD1 p.Ser90Ala (c.268T>G) is associated with Joubert syndrome, orofaciodigital syndrome I (ClinVar).

How common is OFD1 p.Ser90Ala (c.268T>G) in the general population?

OFD1 p.Ser90Ala (c.268T>G) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about OFD1 p.Ser90Ala (c.268T>G)?

AlphaMissense predicts likely benign (score 0.1886) — an in-silico prediction, not a clinical call.

OFD1 p.Ser90Ala

c.268T>G · rs2518759307 · VCV2944190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.1886	likely benign
REVEL	0.652	pathogenic-leaning
SaProt	LLR -7.98	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 25 kb · p 0.12 · regional, not allelic
Overall
CADD	23.1	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 0.000112% European (non-Finnish) · 1/894,548 alleles

Overall 8.26e-05% 1/1,210,336 alleles · very rare exomes 1/1,097,158 · genomes 0/113,178 · joint denominator

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.Ser90Ala
Coding: c.268T>G
MANE Select: NM_003611
dbSNP: rs2518759307
Type: single nucleotide variant
Location: chrX:13736634 (GRCh38)
Structure: AlphaFold pLDDT 68.41
Residue 90: the lish domain

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 p.Ser90= Likely benign ★★ same residue
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

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-ser90ala (accessed [today's date]).

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