Is CRHR2 p.Pro63Arg (c.188C>G) pathogenic?

CRHR2 p.Pro63Arg (c.188C>G) is classified Uncertain significance in CRHR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.1898); Ultra-rare (popmax 0.0164%, mid).

How common is CRHR2 p.Pro63Arg (c.188C>G) in the general population?

CRHR2 p.Pro63Arg (c.188C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CRHR2 p.Pro63Arg (c.188C>G)?

AlphaMissense predicts likely benign (score 0.1898) — an in-silico prediction, not a clinical call.

CRHR2 p.Pro63Arg

c.188C>G · VCV4234123

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1898 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1898	likely benign
REVEL	0.433	indeterminate
SaProt	LLR -11.15	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 29 kb · p 0.65 · regional, not allelic
Overall
CADD	28.0	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00211% 34/1,611,822 alleles · ultra-rare exomes 29/1,459,626 · genomes 5/152,196 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
Remaining individualsnot grpmax-eligible	0.00321%	31,190
European (non-Finnish)	0.00246%	40,670
Admixed American	0.00167%	59,794
African / African-American	0.00134%	74,848

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: CRHR2
Protein: p.Pro63Arg
Coding: c.188C>G
MANE Select: NM_001883
Type: single nucleotide variant
Location: chr7:30681956 (GRCh38)
Gene constraint: LOEUF 1.221 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.80 · 6 PDB
Residue 63: a β-strand

Full CRHR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CRHR2 p.Arg114Cys Uncertain significance ★ ⚠ same type
CRHR2 p.Arg142Trp Uncertain significance ★ same type
CRHR2 p.Arg145Cys Uncertain significance ★ same type
CRHR2 p.Arg145Leu Uncertain significance ★ ⚠ same type
CRHR2 p.Arg148Trp Uncertain significance ★ ⚠ same type
CRHR2 p.Arg221Cys Uncertain significance ★ ⚠ same type
CRHR2 p.Arg221His Uncertain significance ★ ⚠ same type
CRHR2 p.Arg223His 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/crhr2-p-pro63arg (accessed [today's date]).

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