Is OFD1 p.Cys766Phe (c.2297G>T) pathogenic?

OFD1 p.Cys766Phe (c.2297G>T) is classified Uncertain significance in OFD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-02). AlphaMissense: likely benign (0.0814); Very rare (popmax 0.00876%, amr); Associated with orofaciodigital syndrome I.

What condition is associated with OFD1 p.Cys766Phe (c.2297G>T)?

OFD1 p.Cys766Phe (c.2297G>T) is associated with orofaciodigital syndrome I, Simpson-Golabi-Behmel syndrome type 2, retinitis pigmentosa 23 (ClinVar).

How common is OFD1 p.Cys766Phe (c.2297G>T) in the general population?

OFD1 p.Cys766Phe (c.2297G>T) is very rare (popmax 0.00876%, amr) (gnomAD).

What do computational predictors say about OFD1 p.Cys766Phe (c.2297G>T)?

AlphaMissense predicts likely benign (score 0.0814) — an in-silico prediction, not a clinical call.

OFD1 p.Cys766Phe

c.2297G>T · rs774888576 · VCV588180

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0814 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00876%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

orofaciodigital syndrome I

Computational evidence

Protein change
AlphaMissense	0.0814	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -5.43	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 0.11	GERP 3.4
Regional constraint	o/e 1.02	unconstrained · MANE · 8,639 bp · p 0.77 · regional, not allelic
Overall
CADD	14.99	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 0.00876% Admixed American · 4/45,641 alleles

Filtering AF 0.00294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00178%

Overall 0.000414% 5/1,208,899 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00876%	11,410
African / African-American	0.00176%	56,955

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.Cys766Phe
Coding: c.2297G>T
MANE Select: NM_003611
dbSNP: rs774888576
Type: single nucleotide variant
Location: chrX:13761121 (GRCh38)
Structure: AlphaFold pLDDT 68.41
Residue 766: 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

orofaciodigital syndrome I — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Simpson-Golabi-Behmel syndrome type 2 retinitis pigmentosa 23 Joubert syndrome 10 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.Gln966Ter 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-cys766phe (accessed [today's date]).

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