Is ANKH p.Ile96= (c.288C>T) pathogenic?

ANKH p.Ile96= (c.288C>T) is classified Benign/Likely benign in ANKH (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-06). Ultra-rare (popmax 0.0423%, eas); Associated with craniometaphyseal dysplasia, autosomal dominant.

What condition is associated with ANKH p.Ile96= (c.288C>T)?

ANKH p.Ile96= (c.288C>T) is associated with craniometaphyseal dysplasia, autosomal dominant, chondrocalcinosis 2 (ClinVar).

How common is ANKH p.Ile96= (c.288C>T) in the general population?

ANKH p.Ile96= (c.288C>T) is ultra-rare (popmax 0.0423%, eas) (gnomAD).

ANKH p.Ile96=

c.288C>T · rs373730199 · VCV351560

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0423%, eas)

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 -5.3	GERP -3.5
Overall
CADD	1.31	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0423% East Asian · 19/44,896 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.023%

Overall 0.00359% 58/1,614,098 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0512%	1,953
East Asiangrpmax	0.0423%	2,363
African / African-American	0.00267%	37,464
Admixed American	0.00167%	60,008
South Asian	0.0011%	91,088
European (non-Finnish)	0.000254%	393,349

Remaining individuals 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: ANKH
Protein: p.Ile96=
Coding: c.288C>T
MANE Select: NM_054027
dbSNP: rs373730199
Type: single nucleotide variant
Location: chr5:14769000 (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-ile96 (accessed [today's date]).

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