Is ROGDI p.Ser50Pro (c.148T>C) pathogenic?

ROGDI p.Ser50Pro (c.148T>C) is classified Uncertain significance in ROGDI (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-29). AlphaMissense: likely benign (0.0627); Very rare (popmax 0.00112%, sas); Associated with amelocerebrohypohidrotic syndrome.

What condition is associated with ROGDI p.Ser50Pro (c.148T>C)?

ROGDI p.Ser50Pro (c.148T>C) is associated with amelocerebrohypohidrotic syndrome (ClinVar).

How common is ROGDI p.Ser50Pro (c.148T>C) in the general population?

ROGDI p.Ser50Pro (c.148T>C) is very rare (popmax 0.00112%, sas) (gnomAD).

What do computational predictors say about ROGDI p.Ser50Pro (c.148T>C)?

AlphaMissense predicts likely benign (score 0.0627) — an in-silico prediction, not a clinical call.

ROGDI p.Ser50Pro

c.148T>C · rs2505729263 · VCV2065293

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0627 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amelocerebrohypohidrotic syndrome

Computational evidence

Protein change
AlphaMissense	0.0627	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.94	GERP -2, phastCons 0.99
Regional constraint	o/e 1.35	unconstrained · MANE · 5,108 bp · p 7.6e-12 · regional, not allelic
Overall
CADD	14.32	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00112% South Asian · 1/89,406 alleles

Overall 6.23e-05% 1/1,605,652 alleles · very rare exomes 1/1,453,306 · genomes 0/152,346 · 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.Ser50Pro
Coding: c.148T>C
MANE Select: NM_024589
dbSNP: rs2505729263
Type: single nucleotide variant
Location: chr16:4801555 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.59 · 2 PDB

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.Ser50Cys Uncertain significance ★ ⚠ same residue
ROGDI p.Ser50= Likely benign ★ 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-ser50pro (accessed [today's date]).

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