Is OFD1 p.Ser862Ala (c.2584T>G) pathogenic?

OFD1 p.Ser862Ala (c.2584T>G) is classified Conflicting classifications of pathogenicity in OFD1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-17). AlphaMissense: likely benign (0.0725); Ultra-rare (popmax 0.0123%, afr); Associated with orofaciodigital syndrome I.

What condition is associated with OFD1 p.Ser862Ala (c.2584T>G)?

OFD1 p.Ser862Ala (c.2584T>G) is associated with orofaciodigital syndrome I, Simpson-Golabi-Behmel syndrome type 2, retinitis pigmentosa 23 (ClinVar).

How common is OFD1 p.Ser862Ala (c.2584T>G) in the general population?

OFD1 p.Ser862Ala (c.2584T>G) is ultra-rare (popmax 0.0123%, afr) (gnomAD).

What do computational predictors say about OFD1 p.Ser862Ala (c.2584T>G)?

AlphaMissense predicts likely benign (score 0.0725) — an in-silico prediction, not a clinical call.

OFD1 p.Ser862Ala

c.2584T>G · rs797045846 · VCV211787

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0725 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

orofaciodigital syndrome I

Computational evidence

Protein change
AlphaMissense	0.0725	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -7.08	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 -0.26	GERP -3.1
Regional constraint	o/e 1.02	unconstrained · MANE · 8,639 bp · p 0.77 · regional, not allelic
Overall
CADD	7.699	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 0.0123% African / African-American · 7/57,081 alleles

Filtering AF 0.00568% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00406%

Overall 0.00108% 13/1,204,287 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0123%	8,154
Admixed American	0.00655%	15,263
Remaining individualsnot grpmax-eligible	0.00634%	15,782

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.Ser862Ala
Coding: c.2584T>G
MANE Select: NM_003611
dbSNP: rs797045846
Type: single nucleotide variant
Location: chrX:13763840 (GRCh38)
Structure: AlphaFold pLDDT 68.41
Residue 862: 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 Joubert syndrome

Similar variants

OFD1 p.Ser862= Likely benign ★ 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-ser862ala (accessed [today's date]).

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