Is CRH p.Pro30Arg (c.89C>G) pathogenic?

CRH p.Pro30Arg (c.89C>G) is classified Likely benign in CRH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2017-09-07). AlphaMissense: likely benign (0.0904); Ultra-rare (popmax 0.0273%, nfe); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CRH p.Pro30Arg (c.89C>G)?

CRH p.Pro30Arg (c.89C>G) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CRH p.Pro30Arg (c.89C>G) in the general population?

CRH p.Pro30Arg (c.89C>G) is ultra-rare (popmax 0.0273%, nfe) (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CRH p.Pro30Arg (c.89C>G)?

AlphaMissense predicts likely benign (score 0.0904) — an in-silico prediction, not a clinical call.

CRH p.Pro30Arg

c.89C>G · rs748404250 · VCV183027

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0904 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0273%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.0904	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -6.17	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 6.4	GERP 1.5, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 463 bp · p 0.0045 · regional, not allelic
Overall
CADD	20.6	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 0.0273% European (non-Finnish) · 313/1,146,600 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0238%

Overall 0.0217% 334/1,539,544 alleles · ultra-rare exomes 314/1,387,374 · genomes 20/152,170 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0273%	3,663
Remaining individualsnot grpmax-eligible	0.0217%	4,606
Admixed American	0.0137%	7,294
African / African-American	0.00137%	72,834

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: CRH
Protein: p.Pro30Arg
Coding: c.89C>G
MANE Select: NM_000756
dbSNP: rs748404250
Type: single nucleotide variant
Location: chr8:66177389 (GRCh38)
Gene constraint: LOEUF 1.718 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.82 · 5 PDB
Residue 30: a UniProt-annotated variant site (found in patients with autosomal dominant nocturnal frontal lobe epilepsy; uncertain significance; results in decreased protein levels; decreased protein secretion)

Full CRH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial sleep-related hypermotor epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sleep-related hypermotor epilepsy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CRH p.Ala24= Likely benign ★★ same type
CRH p.Arg152= Benign/Likely benign ★★ same type
CRH p.Gly96= Benign ★★ same type
CRH p.Leu17= Benign ★★ same type
CRH p.Ala140Gly Uncertain significance ★ ⚠ same type
CRH p.Ala177Thr Uncertain significance ★ same type
CRH p.Ala24Thr Uncertain significance ★ ⚠ same type
CRH p.Ala37Val Uncertain significance ★ ⚠ same type

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/crh-p-pro30arg (accessed [today's date]).

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