Is OFD1 p.Ser76Phe (c.227C>T) pathogenic?

OFD1 p.Ser76Phe (c.227C>T) is classified Uncertain significance in OFD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-29). AlphaMissense: ambiguous (0.3944); Very rare (popmax 0.000785%, nfe); Associated with Joubert syndrome.

What condition is associated with OFD1 p.Ser76Phe (c.227C>T)?

OFD1 p.Ser76Phe (c.227C>T) is associated with Joubert syndrome, orofaciodigital syndrome I (ClinVar).

How common is OFD1 p.Ser76Phe (c.227C>T) in the general population?

OFD1 p.Ser76Phe (c.227C>T) is very rare (popmax 0.000785%, nfe) (gnomAD).

What do computational predictors say about OFD1 p.Ser76Phe (c.227C>T)?

AlphaMissense predicts ambiguous (score 0.3944) — an in-silico prediction, not a clinical call.

OFD1 p.Ser76Phe

c.227C>T · rs1569102409 · VCV592034

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000785%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.3944	ambiguous
REVEL	0.774	moderately pathogenic-leaning
SaProt	LLR -8.92	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.04	GERP -0.45
Regional constraint	o/e 0.93	unconstrained · MANE · 25 kb · p 0.12 · regional, not allelic
Overall
CADD	19.92	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 0.000785% European (non-Finnish) · 7/891,324 alleles

Filtering AF 0.000327% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00021%

Overall 0.00064% 7/1,093,584 alleles · very rare

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.Ser76Phe
Coding: c.227C>T
MANE Select: NM_003611
dbSNP: rs1569102409
Type: single nucleotide variant
Location: chrX:13736593 (GRCh38)
Structure: AlphaFold pLDDT 68.41
Residue 76: 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

TRAPPC2 p.Val76Ala 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
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-ser76phe (accessed [today's date]).

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