Is ANKH p.Ala426= (c.1278G>A) pathogenic?

ANKH p.Ala426= (c.1278G>A) is classified Benign/Likely benign in ANKH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-23). Very rare (popmax 0.004%, afr); Associated with chondrocalcinosis 2.

What condition is associated with ANKH p.Ala426= (c.1278G>A)?

ANKH p.Ala426= (c.1278G>A) is associated with chondrocalcinosis 2, craniometaphyseal dysplasia, autosomal dominant (ClinVar).

How common is ANKH p.Ala426= (c.1278G>A) in the general population?

ANKH p.Ala426= (c.1278G>A) is very rare (popmax 0.004%, afr) (gnomAD).

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.Ala426=

c.1278G>A · rs568804732 · VCV351501

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

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 3.3	GERP -2.9, phastCons 1
Overall
CADD	7.199	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/75,044 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00174% 28/1,613,072 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,015
Remaining individualsnot grpmax-eligible	0.0032%	31,218
East Asian	0.00223%	44,866
European (non-Finnish)	0.00178%	56,177
Admixed American	0.00167%	59,910

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.Ala426=
Coding: c.1278G>A
MANE Select: NM_054027
dbSNP: rs568804732
Type: single nucleotide variant
Location: chr5:14712961 (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.Ala426Thr 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-ala426 (accessed [today's date]).

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