Is ROGDI p.Ala140= (c.420T>C) pathogenic?

ROGDI p.Ala140= (c.420T>C) is classified Likely benign in ROGDI (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-26). Ultra-rare (popmax 0.0584%, amr); Associated with amelocerebrohypohidrotic syndrome.

What condition is associated with ROGDI p.Ala140= (c.420T>C)?

ROGDI p.Ala140= (c.420T>C) is associated with amelocerebrohypohidrotic syndrome (ClinVar).

How common is ROGDI p.Ala140= (c.420T>C) in the general population?

ROGDI p.Ala140= (c.420T>C) is ultra-rare (popmax 0.0584%, amr) (gnomAD).

ROGDI p.Ala140=

c.420T>C · rs1464249475 · VCV771822

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0584%, amr)

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 -2.4	GERP -2.6
Overall
CADD	0.216	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0584% Admixed American · 35/59,904 alleles

Filtering AF 0.0432% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0378%

Overall 0.00223% 36/1,612,960 alleles · ultra-rare exomes 5/1,460,820 · genomes 31/152,140 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0584%	1,712
Remaining individualsnot grpmax-eligible	0.0016%	62,428

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.Ala140=
Coding: c.420T>C
MANE Select: NM_024589
dbSNP: rs1464249475
Type: single nucleotide variant
Location: chr16:4799698 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.59 · 2 PDB
Residue 140: an α-helix; a UniProt-annotated variant site (in ktzs; uncertain significance)

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.Ala140Thr Uncertain significance ★ ⚠ 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
ROGDI p.Gln112Ter Pathogenic/Likely pathogenic ★★ same condition
ROGDI p.Gln114Ter 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/rogdi-p-ala140 (accessed [today's date]).

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