Is OFD1 p.Ala449= (c.1347A>G) pathogenic?

OFD1 p.Ala449= (c.1347A>G) is classified Likely benign in OFD1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Very rare (popmax 0.00524%, afr); Associated with orofaciodigital syndrome I.

What condition is associated with OFD1 p.Ala449= (c.1347A>G)?

OFD1 p.Ala449= (c.1347A>G) is associated with orofaciodigital syndrome I, Simpson-Golabi-Behmel syndrome type 2, retinitis pigmentosa 23 (ClinVar).

How common is OFD1 p.Ala449= (c.1347A>G) in the general population?

OFD1 p.Ala449= (c.1347A>G) is very rare (popmax 0.00524%, afr) (gnomAD).

OFD1 p.Ala449=

c.1347A>G · rs151287373 · VCV994698

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00524%, afr)

Conditions

orofaciodigital syndrome I

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -2.1
Overall
CADD	0.721	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00524% African / African-American · 3/57,221 alleles

Filtering AF 0.00274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00315% 38/1,207,403 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00524%	19,074
European (non-Finnish)	0.00381%	26,252
Remaining individualsnot grpmax-eligible	0.00211%	47,484

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.Ala449=
Coding: c.1347A>G
MANE Select: NM_003611
dbSNP: rs151287373
Type: single nucleotide variant
Location: chrX:13756703 (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: Simpson-Golabi-Behmel syndrome type 2 retinitis pigmentosa 23 Joubert syndrome 10 Joubert syndrome

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.Gln966Ter Pathogenic/Likely pathogenic ★★ same condition
OFD1 p.Tyr87Cys 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-ala449 (accessed [today's date]).

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