Is OFD1 p.Ser92Phe (c.275C>T) pathogenic?

OFD1 p.Ser92Phe (c.275C>T) is classified Uncertain significance in OFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-05). AlphaMissense: likely pathogenic (0.7954); Absent from gnomAD v4.1; Associated with Joubert syndrome.

What condition is associated with OFD1 p.Ser92Phe (c.275C>T)?

OFD1 p.Ser92Phe (c.275C>T) is associated with Joubert syndrome, orofaciodigital syndrome I (ClinVar).

How common is OFD1 p.Ser92Phe (c.275C>T) in the general population?

OFD1 p.Ser92Phe (c.275C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about OFD1 p.Ser92Phe (c.275C>T)?

AlphaMissense predicts likely pathogenic (score 0.7954) — an in-silico prediction, not a clinical call.

OFD1 p.Ser92Phe

c.275C>T · rs2146913635 · VCV2014392

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7954 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.7954	likely pathogenic · top 3% in OFD1
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -13.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 25 kb · p 0.12 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: OFD1
Protein: p.Ser92Phe
Coding: c.275C>T
MANE Select: NM_003611
dbSNP: rs2146913635
Type: single nucleotide variant
Location: chrX:13736641 (GRCh38)
Structure: AlphaFold pLDDT 68.41
Residue 92: 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.Ser92= Conflicting classifications of pathogenicity ★ same residue
OFD1 p.Ser92Pro Likely pathogenic ★ same residue
TRAPPC2 p.Glu92Asp Uncertain significance ★ ⚠ 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

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-ser92phe (accessed [today's date]).

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