Is ROGDI p.Phe232Ser (c.695T>C) pathogenic?

ROGDI p.Phe232Ser (c.695T>C) is classified Uncertain significance in ROGDI (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-02). AlphaMissense: likely pathogenic (0.9792); Ultra-rare (popmax 0.0101%, amr); Associated with amelocerebrohypohidrotic syndrome.

What condition is associated with ROGDI p.Phe232Ser (c.695T>C)?

ROGDI p.Phe232Ser (c.695T>C) is associated with amelocerebrohypohidrotic syndrome (ClinVar).

How common is ROGDI p.Phe232Ser (c.695T>C) in the general population?

ROGDI p.Phe232Ser (c.695T>C) is ultra-rare (popmax 0.0101%, amr) (gnomAD).

What do computational predictors say about ROGDI p.Phe232Ser (c.695T>C)?

AlphaMissense predicts likely pathogenic (score 0.9792) — an in-silico prediction, not a clinical call.

ROGDI p.Phe232Ser

c.695T>C · rs776235683 · VCV948480

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9792 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

amelocerebrohypohidrotic syndrome

Computational evidence

Protein change
AlphaMissense	0.9792	likely pathogenic · top 9% in ROGDI
REVEL	0.587	indeterminate
SaProt	LLR -8.44	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.35	unconstrained · MANE · 5,108 bp · p 7.6e-12 · regional, not allelic
Overall
CADD	30.0	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 0.0101% Admixed American · 6/59,468 alleles

Filtering AF 0.00432% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00297%

Overall 0.000437% 7/1,600,098 alleles · ultra-rare exomes 6/1,447,984 · genomes 1/152,114 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0101%	9,911
Remaining individualsnot grpmax-eligible	0.00162%	61,818

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.Phe232Ser
Coding: c.695T>C
MANE Select: NM_024589
dbSNP: rs776235683
Type: single nucleotide variant
Location: chr16:4797938 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.59 · 2 PDB
Residue 232: a β-strand; 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.Phe232= Benign/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
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-phe232ser (accessed [today's date]).

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