Is ROGDI p.Ala2Val (c.5C>T) pathogenic?

ROGDI p.Ala2Val (c.5C>T) is classified Uncertain significance in ROGDI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-06). AlphaMissense: ambiguous (0.5579); Very rare (popmax 0.00211%, sas); Associated with amelocerebrohypohidrotic syndrome.

What condition is associated with ROGDI p.Ala2Val (c.5C>T)?

ROGDI p.Ala2Val (c.5C>T) is associated with amelocerebrohypohidrotic syndrome (ClinVar).

How common is ROGDI p.Ala2Val (c.5C>T) in the general population?

ROGDI p.Ala2Val (c.5C>T) is very rare (popmax 0.00211%, sas) (gnomAD).

What do computational predictors say about ROGDI p.Ala2Val (c.5C>T)?

AlphaMissense predicts ambiguous (score 0.5579) — an in-silico prediction, not a clinical call.

ROGDI p.Ala2Val

c.5C>T · rs2082747617 · VCV1942634

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5579 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00211%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

amelocerebrohypohidrotic syndrome

Computational evidence

Protein change
AlphaMissense	0.5579	ambiguous
REVEL	0.137	moderately benign-leaning
SaProt	LLR -7.78	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 0.36, phastCons 1
Regional constraint	o/e 1.35	unconstrained · MANE · 5,108 bp · p 7.6e-12 · regional, not allelic
Overall
CADD	19.32	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 0.00211% South Asian · 1/47,372 alleles

Overall 0.00023% 3/1,302,826 alleles · very rare exomes 2/1,151,158 · genomes 1/151,668 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00211%	47,372
African / African-American	0.00153%	65,390
European (non-Finnish)	9.82e-05%	1,018,396

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.Ala2Val
Coding: c.5C>T
MANE Select: NM_024589
dbSNP: rs2082747617
Type: single nucleotide variant
Location: chr16:4802567 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.59 · 2 PDB
Residue 2: an α-helix; a modified residue (n-acetylalanine)

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.Ala2Thr 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-ala2val (accessed [today's date]).

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