Is OFD1 p.Ser399Phe (c.1196C>T) pathogenic?

OFD1 p.Ser399Phe (c.1196C>T) is classified Uncertain significance in OFD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-04). AlphaMissense: likely benign (0.1891); Very rare (popmax 0.000908%, nfe); Associated with Joubert syndrome.

What condition is associated with OFD1 p.Ser399Phe (c.1196C>T)?

OFD1 p.Ser399Phe (c.1196C>T) is associated with Joubert syndrome, orofaciodigital syndrome I, primary ciliary dyskinesia (ClinVar).

How common is OFD1 p.Ser399Phe (c.1196C>T) in the general population?

OFD1 p.Ser399Phe (c.1196C>T) is very rare (popmax 0.000908%, nfe) (gnomAD).

What do computational predictors say about OFD1 p.Ser399Phe (c.1196C>T)?

AlphaMissense predicts likely benign (score 0.1891) — an in-silico prediction, not a clinical call.

OFD1 p.Ser399Phe

c.1196C>T · rs748851759 · VCV1746061

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000908%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.1891	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -6.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.016	GERP -2.2, phastCons 0.023
Regional constraint	o/e 0.93	unconstrained · MANE · 25 kb · p 0.12 · regional, not allelic
Overall
CADD	19.26	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.000908% European (non-Finnish) · 8/881,331 alleles

Filtering AF 0.00039% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000282%

Overall 0.000669% 8/1,195,184 alleles · very rare exomes 6/1,082,390 · genomes 2/112,794 · 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.Ser399Phe
Coding: c.1196C>T
MANE Select: NM_003611
dbSNP: rs748851759
Type: single nucleotide variant
Location: chrX:13755217 (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 primary ciliary dyskinesia

Similar variants

OFD1 p.Ser399Cys Uncertain significance ★ ⚠ same residue
OFD1 p.Ser399= 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

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-ser399phe (accessed [today's date]).

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