Is OFD1 p.Arg602Cys (c.1804C>T) pathogenic?

OFD1 p.Arg602Cys (c.1804C>T) is classified Conflicting classifications of pathogenicity in OFD1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-13). AlphaMissense: likely benign (0.1116); Ultra-rare (popmax 0.0229%, mid); Associated with Joubert syndrome.

What condition is associated with OFD1 p.Arg602Cys (c.1804C>T)?

OFD1 p.Arg602Cys (c.1804C>T) is associated with Joubert syndrome, Simpson-Golabi-Behmel syndrome type 2, retinitis pigmentosa 23 (ClinVar).

How common is OFD1 p.Arg602Cys (c.1804C>T) in the general population?

OFD1 p.Arg602Cys (c.1804C>T) is ultra-rare (popmax 0.0229%, mid) (gnomAD).

What do computational predictors say about OFD1 p.Arg602Cys (c.1804C>T)?

AlphaMissense predicts likely benign (score 0.1116) — an in-silico prediction, not a clinical call.

OFD1 p.Arg602Cys

c.1804C>T · VCV3598087

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1116 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.1116	likely benign
REVEL	0.258	benign-leaning
SaProt	LLR -9.01	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 0.12	GERP -2.5
Regional constraint	o/e 0.93	unconstrained · MANE · 25 kb · p 0.12 · regional, not allelic
Overall
CADD	4.553	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 0.0229% Middle Eastern · 1/4,375 alleles

Filtering AF 0.00151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00128%

Overall 0.00198% 24/1,209,758 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0229%	4,375
East Asian	0.00296%	33,776
European (non-Finnish)	0.00235%	42,624
Remaining individualsnot grpmax-eligible	0.0021%	47,591

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.Arg602Cys
Coding: c.1804C>T
MANE Select: NM_003611
Type: single nucleotide variant
Location: chrX:13760264 (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: Simpson-Golabi-Behmel syndrome type 2 retinitis pigmentosa 23 Joubert syndrome 10 orofaciodigital syndrome I

Similar variants

OFD1 p.Arg602fs Likely pathogenic ★ 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.Gln966Ter 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-arg602cys (accessed [today's date]).

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