Is ROGDI p.Ala223= (c.669G>A) pathogenic?

ROGDI p.Ala223= (c.669G>A) is classified Likely benign in ROGDI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-01). Ultra-rare (popmax 0.0665%, mid); Associated with amelocerebrohypohidrotic syndrome.

What condition is associated with ROGDI p.Ala223= (c.669G>A)?

ROGDI p.Ala223= (c.669G>A) is associated with amelocerebrohypohidrotic syndrome (ClinVar).

How common is ROGDI p.Ala223= (c.669G>A) in the general population?

ROGDI p.Ala223= (c.669G>A) is ultra-rare (popmax 0.0665%, mid) (gnomAD).

ROGDI p.Ala223=

c.669G>A · rs143402543 · VCV728037

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0665%, mid)

Conditions

amelocerebrohypohidrotic syndrome

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 -20	GERP -3
Overall
CADD	0.019	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0665% Middle Eastern · 4/6,016 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00548% 88/1,605,760 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0665%	1,504
African / African-American	0.0347%	2,882
Remaining individualsnot grpmax-eligible	0.00643%	15,543
East Asian	0.00447%	22,357
European (non-Finnish)	0.00426%	23,493
Admixed American	0.00167%	59,714
South Asian	0.00111%	90,324

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: ROGDI
Protein: p.Ala223=
Coding: c.669G>A
MANE Select: NM_024589
dbSNP: rs143402543
Type: single nucleotide variant
Location: chr16:4797964 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.59 · 2 PDB
Residue 223: a β-strand; a UniProt-annotated variant site (in ktzs; uncertain significance); a UniProt-annotated variant site (in ktzs)

Full ROGDI gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

amelocerebrohypohidrotic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ROGDI p.Ala223Thr Uncertain significance ★★ ⚠ same residue
ROGDI p.Ala223Ser Uncertain significance ★ ⚠ same residue
ROGDI p.Ala223fs Pathogenic ★ same residue
ROGDI c.117+1G>A Pathogenic/Likely pathogenic ★★ same condition
ROGDI c.46-2A>G Likely pathogenic ★★ same condition
ROGDI c.531+5G>C Likely pathogenic ★★ same condition
ROGDI c.645+2T>A Likely pathogenic ★★ same condition
ROGDI p.Arg157Ter 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/rogdi-p-ala223 (accessed [today's date]).

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