Is ROGDI p.Val192Asp (c.575T>A) pathogenic?

ROGDI p.Val192Asp (c.575T>A) is classified Uncertain significance in ROGDI (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-23). AlphaMissense: likely pathogenic (0.9757); Very rare (popmax 8.47e-05%, nfe); Associated with amelocerebrohypohidrotic syndrome.

What condition is associated with ROGDI p.Val192Asp (c.575T>A)?

ROGDI p.Val192Asp (c.575T>A) is associated with amelocerebrohypohidrotic syndrome (ClinVar).

How common is ROGDI p.Val192Asp (c.575T>A) in the general population?

ROGDI p.Val192Asp (c.575T>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ROGDI p.Val192Asp (c.575T>A)?

AlphaMissense predicts likely pathogenic (score 0.9757) — an in-silico prediction, not a clinical call.

ROGDI p.Val192Asp

c.575T>A · rs1363228432 · VCV2134926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9757 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

amelocerebrohypohidrotic syndrome

Computational evidence

Protein change
AlphaMissense	0.9757	likely pathogenic · top 10% in ROGDI
REVEL	0.471	indeterminate
SaProt	LLR -13.18	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.35	unconstrained · MANE · 5,108 bp · p 7.6e-12 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,946 alleles

Overall 6.84e-05% 1/1,461,750 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: ROGDI
Protein: p.Val192Asp
Coding: c.575T>A
MANE Select: NM_024589
dbSNP: rs1363228432
Type: single nucleotide variant
Location: chr16:4798141 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.59 · 2 PDB
Residue 192: 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.Val192Ile 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-val192asp (accessed [today's date]).

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