Is OFD1 p.Ala186Pro (c.556G>C) pathogenic?

OFD1 p.Ala186Pro (c.556G>C) is classified Uncertain significance in OFD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-27). AlphaMissense: ambiguous (0.4132); Very rare (popmax 0.00112%, nfe); Associated with Joubert syndrome.

What condition is associated with OFD1 p.Ala186Pro (c.556G>C)?

OFD1 p.Ala186Pro (c.556G>C) is associated with Joubert syndrome, orofaciodigital syndrome I (ClinVar).

How common is OFD1 p.Ala186Pro (c.556G>C) in the general population?

OFD1 p.Ala186Pro (c.556G>C) is very rare (popmax 0.00112%, nfe) (gnomAD).

What do computational predictors say about OFD1 p.Ala186Pro (c.556G>C)?

AlphaMissense predicts ambiguous (score 0.4132) — an in-silico prediction, not a clinical call.

OFD1 p.Ala186Pro

c.556G>C · rs1161161896 · VCV1377167

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4132 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, nfe)

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.4132	ambiguous
REVEL	0.299	indeterminate
SaProt	LLR -6.65	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -1.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 25 kb · p 0.12 · regional, not allelic
Overall
CADD	18.72	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 0.00112% European (non-Finnish) · 10/890,074 alleles

Filtering AF 0.000568% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000414%

Overall 0.000917% 10/1,090,847 alleles · very rare

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.Ala186Pro
Coding: c.556G>C
MANE Select: NM_003611
dbSNP: rs1161161896
Type: single nucleotide variant
Location: chrX:13746357 (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: orofaciodigital syndrome I

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.Tyr87Cys Pathogenic ★★ ⚠ same condition
OFD1 c.2388-3T>C Uncertain significance ★★ 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-ala186pro (accessed [today's date]).

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