Is ANKH p.Ala321= (c.963A>G) pathogenic?

ANKH p.Ala321= (c.963A>G) is classified Benign in ANKH (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). Common (popmax 15.9%, amr) — too common for a highly-penetrant pathogenic allele; Associated with chondrocalcinosis 2.

What condition is associated with ANKH p.Ala321= (c.963A>G)?

ANKH p.Ala321= (c.963A>G) is associated with chondrocalcinosis 2, craniometaphyseal dysplasia, autosomal dominant (ClinVar).

How is Familial calcium pyrophosphate deposition inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

ANKH p.Ala321=

Q: How common is ANKH p.Ala321= (c.963A>G) in the general population?

ANKH p.Ala321= (c.963A>G) is common (popmax 15.9%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.963A>G · rs2288474 · VCV351512

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 15.9%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

chondrocalcinosis 2

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 -15	GERP -3.5
Overall
CADD	0.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 15.9% Admixed American · 9,565/60,002 alleles

Filtering AF 15.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 15.6%

Overall 5.28% 85,159/1,613,956 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	15.9%	6
East Asian	14.3%	7
African / African-American	8.16%	12
Amishnot grpmax-eligible	7.35%	14
Remaining individualsnot grpmax-eligible	5.07%	20
South Asian	5.05%	20
European (non-Finnish)	4.42%	23
Finnishnot grpmax-eligible	3.39%	29
Middle Eastern	3.37%	30
Ashkenazi Jewishnot grpmax-eligible	2.41%	42

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: ANKH
Protein: p.Ala321=
Coding: c.963A>G
MANE Select: NM_054027
dbSNP: rs2288474
Type: single nucleotide variant
Location: chr5:14741875 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.57

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

Disease context

chondrocalcinosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: craniometaphyseal dysplasia, autosomal dominant

For Familial calcium pyrophosphate deposition (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult

Similar variants

ANKH p.Ala321Glu Uncertain significance ★ ⚠ same residue
ANKH c.1142-4A>G Pathogenic/Likely pathogenic ★★ same condition
ANKH c.*3752G>A Uncertain significance ★★ same condition
ANKH p.Val313Met Uncertain significance ★★ ⚠ same condition
ANKH c.1011+15T>G Benign ★★ same condition
ANKH c.1012-11T>G Benign/Likely benign ★★ same condition
ANKH c.1265+6T>C Benign ★★ same condition
ANKH c.1266-6C>T Benign/Likely benign ★★ 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/ankh-p-ala321 (accessed [today's date]).

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