Is CP p.His997= (c.2991T>C) pathogenic?

CP p.His997= (c.2991T>C) is classified Benign/Likely benign in CP (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 5.2%, mid) — too common for a highly-penetrant pathogenic allele; Associated with aceruloplasminemia.

What condition is associated with CP p.His997= (c.2991T>C)?

CP p.His997= (c.2991T>C) is associated with aceruloplasminemia (ClinVar).

How is Aceruloplasminemia inherited?

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

CP p.His997=

Q: How common is CP p.His997= (c.2991T>C) in the general population?

CP p.His997= (c.2991T>C) is common (popmax 5.2%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2991T>C · rs34394958 · VCV128841

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 5.2%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

aceruloplasminemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.38	GERP -3.9, phastCons 0.68
Overall
CADD	5.128	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.2% Middle Eastern · 315/6,062 alleles

Filtering AF 4.72% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.65%

Overall 4.16% 67,089/1,613,350 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	6.26%	16
Middle Easterngrpmax	5.2%	19
European (non-Finnish)	4.69%	21
South Asian	3.46%	29
Remaining individualsnot grpmax-eligible	3.45%	29
Admixed American	1.7%	59
Ashkenazi Jewishnot grpmax-eligible	1.34%	75
African / African-American	0.904%	111
Amishnot grpmax-eligible	0.11%	912
East Asian	0.0111%	8,974

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CP
Protein: p.His997=
Coding: c.2991T>C
MANE Select: NM_000096
dbSNP: rs34394958
Type: single nucleotide variant
Location: chr3:149177867 (GRCh38)
Gene constraint: LOEUF 0.624 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.79 · 4 PDB
Residue 997: a β-strand; a binding site; the plastocyanin-like 6 domain

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

Disease context

aceruloplasminemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Aceruloplasminemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult, Elderly
Prevalence: 1-9 / 1 000 000 (Japan)

Similar variants

CP p.His997Tyr Uncertain significance ★★ ⚠ same residue
CP c.1208+1G>A Pathogenic ★★ same condition
CP c.2879-1G>T Likely pathogenic ★★ same condition
CP p.Arg901Ter Pathogenic ★★ same condition
CP p.Gly195Arg Likely pathogenic ★★ same condition
CP p.Gly650Arg Pathogenic/Likely pathogenic ★★ same condition
CP p.Gly708Ser Pathogenic ★★ same condition
CP p.Leu919Pro 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/cp-p-his997 (accessed [today's date]).

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