Is OFD1 p.Arg487Trp (c.1459C>T) pathogenic?

OFD1 p.Arg487Trp (c.1459C>T) is classified Uncertain significance in OFD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-15). AlphaMissense: likely benign (0.0624); Ultra-rare (popmax 0.023%, mid); Associated with orofaciodigital syndrome I.

What condition is associated with OFD1 p.Arg487Trp (c.1459C>T)?

OFD1 p.Arg487Trp (c.1459C>T) is associated with orofaciodigital syndrome I, primary ciliary dyskinesia, Joubert syndrome (ClinVar).

How common is OFD1 p.Arg487Trp (c.1459C>T) in the general population?

OFD1 p.Arg487Trp (c.1459C>T) is ultra-rare (popmax 0.023%, mid) (gnomAD).

What do computational predictors say about OFD1 p.Arg487Trp (c.1459C>T)?

AlphaMissense predicts likely benign (score 0.0624) — an in-silico prediction, not a clinical call.

OFD1 p.Arg487Trp

c.1459C>T · rs777967128 · VCV2928400

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0624 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.023%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

orofaciodigital syndrome I

Computational evidence

Protein change
AlphaMissense	0.0624	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -9.00	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 0.92	GERP -0.005, phastCons 0.027
Regional constraint	o/e 0.93	unconstrained · MANE · 25 kb · p 0.12 · regional, not allelic
Overall
CADD	8.815	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 0.023% Middle Eastern · 1/4,354 alleles

Filtering AF 0.000474% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000343%

Overall 0.000994% 12/1,207,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.023%	4,354
African / African-American	0.00177%	56,415
South Asian	0.00176%	56,699
European (non-Finnish)	0.00101%	99,357

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.Arg487Trp
Coding: c.1459C>T
MANE Select: NM_003611
dbSNP: rs777967128
Type: single nucleotide variant
Location: chrX:13757707 (GRCh38)
Structure: AlphaFold pLDDT 68.41

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: primary ciliary dyskinesia Joubert syndrome

Similar variants

OFD1 p.Arg487Gln Benign/Likely benign ★★ same residue
OFD1 p.Arg487Pro 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-arg487trp (accessed [today's date]).

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