Is OFD1 p.Ser778Ala (c.2332T>G) pathogenic?

OFD1 p.Ser778Ala (c.2332T>G) is classified Uncertain significance in OFD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-04). AlphaMissense: likely benign (0.0844); Very rare (popmax 0.000559%, nfe); Associated with Joubert syndrome.

What condition is associated with OFD1 p.Ser778Ala (c.2332T>G)?

OFD1 p.Ser778Ala (c.2332T>G) is associated with Joubert syndrome, orofaciodigital syndrome I, primary ciliary dyskinesia (ClinVar).

How common is OFD1 p.Ser778Ala (c.2332T>G) in the general population?

OFD1 p.Ser778Ala (c.2332T>G) is very rare (popmax 0.000559%, nfe) (gnomAD).

What do computational predictors say about OFD1 p.Ser778Ala (c.2332T>G)?

AlphaMissense predicts likely benign (score 0.0844) — an in-silico prediction, not a clinical call.

OFD1 p.Ser778Ala

c.2332T>G · rs1306533962 · VCV2923093

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000559%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.0844	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -7.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.95	GERP -0.31, phastCons 0.006
Regional constraint	o/e 1.02	unconstrained · MANE · 8,639 bp · p 0.77 · regional, not allelic
Overall
CADD	8.084	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 0.000559% European (non-Finnish) · 5/894,489 alleles

Filtering AF 0.000164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000119%

Overall 0.000496% 6/1,210,441 alleles · very rare exomes 6/1,097,114 · genomes 0/113,327 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,605
European (non-Finnish)grpmax	0.000559%	178,898

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser778Ala
Coding: c.2332T>G
MANE Select: NM_003611
dbSNP: rs1306533962
Type: single nucleotide variant
Location: chrX:13761156 (GRCh38)
Structure: AlphaFold pLDDT 68.41
Residue 778: the 'mediates the interaction with sdccag8' region; the 'disordered' region

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 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-ser778ala (accessed [today's date]).

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