Is ROGDI p.Pro252= (c.756C>G) pathogenic?

ROGDI p.Pro252= (c.756C>G) is classified Likely benign in ROGDI (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-19). Ultra-rare (popmax 0.0267%, eas); Associated with amelocerebrohypohidrotic syndrome.

What condition is associated with ROGDI p.Pro252= (c.756C>G)?

ROGDI p.Pro252= (c.756C>G) is associated with amelocerebrohypohidrotic syndrome (ClinVar).

How common is ROGDI p.Pro252= (c.756C>G) in the general population?

ROGDI p.Pro252= (c.756C>G) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

ROGDI p.Pro252=

c.756C>G · rs781037239 · VCV767159

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

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 -2.1	GERP -3.3
Overall
CADD	2.463	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% East Asian · 12/44,884 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.000868% 14/1,613,536 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,740
Remaining individualsnot grpmax-eligible	0.0032%	31,240

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.Pro252=
Coding: c.756C>G
MANE Select: NM_024589
dbSNP: rs781037239
Type: single nucleotide variant
Location: chr16:4797780 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.59 · 2 PDB
Residue 252: 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.Pro252Arg Uncertain significance ★ ⚠ same residue
ROGDI p.Pro252Thr 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

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-pro252 (accessed [today's date]).

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