Is CIROP p.His664Gln (c.1992T>G) pathogenic?

CIROP p.His664Gln (c.1992T>G) is classified Likely benign in CIROP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-01-05). AlphaMissense: likely benign (0.2018); Rare (popmax 0.538%, afr); Associated with CIROP-related disorder.

What condition is associated with CIROP p.His664Gln (c.1992T>G)?

CIROP p.His664Gln (c.1992T>G) is associated with CIROP-related disorder (ClinVar).

How common is CIROP p.His664Gln (c.1992T>G) in the general population?

CIROP p.His664Gln (c.1992T>G) is rare (popmax 0.538%, afr) (gnomAD).

What do computational predictors say about CIROP p.His664Gln (c.1992T>G)?

AlphaMissense predicts likely benign (score 0.2018) — an in-silico prediction, not a clinical call.

CIROP p.His664Gln

c.1992T>G · rs187174627 · VCV3054769

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2018 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.538%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

CIROP-related disorder

Computational evidence

Protein change
AlphaMissense	0.2018	likely benign
SaProt	LLR -4.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.98	GERP -4.2, phastCons 1
Regional constraint	o/e 1.77	unconstrained · MANE · 5,635 bp · p 1.3e-32 · regional, not allelic
Overall
CADD	16.13	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 0.538% African / African-American · 262/48,732 alleles

Filtering AF 0.484% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.463%

Overall 0.0724% 289/399,132 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.538%	186
Admixed American	0.066%	1,515
Remaining individualsnot grpmax-eligible	0.0595%	1,681
European (non-Finnish)	0.000442%	226,074

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: CIROP
Protein: p.His664Gln
Coding: c.1992T>G
MANE Select: NM_001354640
dbSNP: rs187174627
Type: single nucleotide variant
Location: chr14:23100669 (GRCh38)
Structure: AlphaFold pLDDT 73.73
Residue 664: a UniProt-annotated variant site (in htx12)

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

Disease context

CIROP-related disorder

Similar variants

CIROP c.988+1G>C Pathogenic ★ same type
CIROP p.Gln528Ter Likely pathogenic ★ same type
CIROP p.Glu376Lys Likely pathogenic ★ ⚠ same type
CIROP c.2159+2T>A Uncertain significance ★ same type
CIROP p.Arg22Ter Conflicting classifications of pathogenicity ★ same type
CIROP p.Gly180Arg Uncertain significance ★ ⚠ same type
CIROP p.Gly511Glu Uncertain significance ★ same type
CIROP p.Ser31Phe Conflicting classifications of pathogenicity ★ ⚠ 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/cirop-p-his664gln (accessed [today's date]).

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