Is ROGDI p.Pro185Ser (c.553C>T) pathogenic?

ROGDI p.Pro185Ser (c.553C>T) is classified Uncertain significance in ROGDI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-07-18). AlphaMissense: ambiguous (0.3467); Very rare (popmax 0.005%, amr); Associated with amelocerebrohypohidrotic syndrome.

What condition is associated with ROGDI p.Pro185Ser (c.553C>T)?

ROGDI p.Pro185Ser (c.553C>T) is associated with amelocerebrohypohidrotic syndrome (ClinVar).

How common is ROGDI p.Pro185Ser (c.553C>T) in the general population?

ROGDI p.Pro185Ser (c.553C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about ROGDI p.Pro185Ser (c.553C>T)?

AlphaMissense predicts ambiguous (score 0.3467) — an in-silico prediction, not a clinical call.

ROGDI p.Pro185Ser

c.553C>T · rs775198813 · VCV626007

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3467 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

amelocerebrohypohidrotic syndrome

Computational evidence

Protein change
AlphaMissense	0.3467	ambiguous
REVEL	0.545	indeterminate
SaProt	LLR -10.15	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	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	23.8	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 0.005% Admixed American · 3/59,998 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000372% 6/1,613,868 alleles · very rare exomes 6/1,461,546 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,999
Remaining individualsnot grpmax-eligible	0.0032%	31,244
East Asian	0.00223%	44,866

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.Pro185Ser
Coding: c.553C>T
MANE Select: NM_024589
dbSNP: rs775198813
Type: single nucleotide variant
Location: chr16:4798163 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.59 · 2 PDB
Residue 185: an α-helix; 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.Pro185Arg Uncertain significance ★★ ⚠ same residue
ROGDI p.Pro185= Likely benign ★★ same residue
ROGDI p.Pro185Leu 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-pro185ser (accessed [today's date]).

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