Is ROGDI p.Ala29Pro (c.85G>C) pathogenic?

ROGDI p.Ala29Pro (c.85G>C) is classified Uncertain significance in ROGDI (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: ambiguous (0.3799); Very rare (popmax 0.000262%, nfe); Associated with amelocerebrohypohidrotic syndrome.

What condition is associated with ROGDI p.Ala29Pro (c.85G>C)?

ROGDI p.Ala29Pro (c.85G>C) is associated with amelocerebrohypohidrotic syndrome (ClinVar).

How common is ROGDI p.Ala29Pro (c.85G>C) in the general population?

ROGDI p.Ala29Pro (c.85G>C) is very rare (popmax 0.000262%, nfe) (gnomAD).

What do computational predictors say about ROGDI p.Ala29Pro (c.85G>C)?

AlphaMissense predicts ambiguous (score 0.3799) — an in-silico prediction, not a clinical call.

ROGDI p.Ala29Pro

c.85G>C · rs376839753 · VCV2014447

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3799 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000262%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

amelocerebrohypohidrotic syndrome

Computational evidence

Protein change
AlphaMissense	0.3799	ambiguous
REVEL	0.278	benign-leaning
SaProt	LLR -8.25	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.22, phastCons 1
Regional constraint	o/e 1.35	unconstrained · MANE · 5,108 bp · p 7.6e-12 · regional, not allelic
Overall
CADD	22.1	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 0.000262% European (non-Finnish) · 3/1,146,108 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000196% 3/1,533,612 alleles · very rare exomes 3/1,381,520 · genomes 0/152,092 · joint denominator

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.Ala29Pro
Coding: c.85G>C
MANE Select: NM_024589
dbSNP: rs376839753
Type: single nucleotide variant
Location: chr16:4802414 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.59 · 2 PDB
Residue 29: 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.Ala29Thr Uncertain significance ★★ ⚠ same residue
ROGDI p.Ala29Gly Uncertain significance ★ ⚠ same residue
ROGDI p.Ala29Val 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

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-ala29pro (accessed [today's date]).

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