Is ANKH p.Ser123= (c.369G>A) pathogenic?

ANKH p.Ser123= (c.369G>A) is classified Benign/Likely benign in ANKH (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-18). Rare (popmax 0.251%, afr); Associated with craniometaphyseal dysplasia, autosomal dominant.

What condition is associated with ANKH p.Ser123= (c.369G>A)?

ANKH p.Ser123= (c.369G>A) is associated with craniometaphyseal dysplasia, autosomal dominant, chondrocalcinosis 2 (ClinVar).

How common is ANKH p.Ser123= (c.369G>A) in the general population?

ANKH p.Ser123= (c.369G>A) is rare (popmax 0.251%, afr) (gnomAD).

ANKH p.Ser123=

c.369G>A · rs145463643 · VCV769645

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.251%, afr)

Conditions

craniometaphyseal dysplasia, autosomal dominant

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	0.57	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.251% African / African-American · 188/75,028 alleles

Filtering AF 0.221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.21%

Overall 0.0162% 261/1,614,118 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.251%	399
South Asian	0.0461%	2,168
Remaining individualsnot grpmax-eligible	0.024%	4,167
Admixed American	0.01%	10,004
East Asian	0.00668%	14,960
European (non-Finnish)	0.000593%	168,573

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.Ser123=
Coding: c.369G>A
MANE Select: NM_054027
dbSNP: rs145463643
Type: single nucleotide variant
Location: chr5:14758543 (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

craniometaphyseal dysplasia, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: chondrocalcinosis 2

Similar variants

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
ANKH c.1365+13C>T 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-ser123 (accessed [today's date]).

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