Is OFD1 p.Arg726= (c.2178C>T) pathogenic?

OFD1 p.Arg726= (c.2178C>T) is classified Likely benign in OFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-21). Very rare (popmax 0.00872%, amr); Associated with Joubert syndrome.

What condition is associated with OFD1 p.Arg726= (c.2178C>T)?

OFD1 p.Arg726= (c.2178C>T) is associated with Joubert syndrome, orofaciodigital syndrome I (ClinVar).

How common is OFD1 p.Arg726= (c.2178C>T) in the general population?

OFD1 p.Arg726= (c.2178C>T) is very rare (popmax 0.00872%, amr) (gnomAD).

OFD1 p.Arg726=

c.2178C>T · rs758869308 · VCV2925839

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00872%, amr)

Conditions

Joubert syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.9	GERP -1.6
Overall
CADD	1.266	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00872% Admixed American · 4/45,856 alleles

Filtering AF 0.00293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00177%

Overall 0.000496% 6/1,209,413 alleles · very rare exomes 5/1,097,560 · genomes 1/111,853 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00872%	11,464
South Asian	0.00176%	56,801
European (non-Finnish)	0.000112%	894,678

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.Arg726=
Coding: c.2178C>T
MANE Select: NM_003611
dbSNP: rs758869308
Type: single nucleotide variant
Location: chrX:13760638 (GRCh38)
Structure: AlphaFold pLDDT 68.41
Residue 726: 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

Similar variants

OFD1 p.Arg726Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
OFD1 p.Arg726His Conflicting classifications of pathogenicity ★ ⚠ 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-arg726 (accessed [today's date]).

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