Is ANKH p.Leu135= (c.405C>T) pathogenic?

ANKH p.Leu135= (c.405C>T) is classified Benign in ANKH (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-20). Low-frequency (popmax 3.26%, afr); Associated with chondrocalcinosis 2.

What condition is associated with ANKH p.Leu135= (c.405C>T)?

ANKH p.Leu135= (c.405C>T) is associated with chondrocalcinosis 2, craniometaphyseal dysplasia, autosomal dominant (ClinVar).

How common is ANKH p.Leu135= (c.405C>T) in the general population?

ANKH p.Leu135= (c.405C>T) is low-frequency (popmax 3.26%, 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.Leu135=

c.405C>T · rs149656955 · VCV351555

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.26%, 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 -5	GERP -3.5
Overall
CADD	2.783	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.26% African / African-American · 2,444/75,010 alleles

Filtering AF 3.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.11%

Overall 0.174% 2,802/1,614,042 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.26%	31
Admixed American	0.235%	426
Remaining individualsnot grpmax-eligible	0.224%	447
Middle Eastern	0.0495%	2,021
European (non-Finnish)	0.00585%	17,101
South Asian	0.00439%	22,769
East Asian	0.00223%	44,884

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.Leu135=
Coding: c.405C>T
MANE Select: NM_054027
dbSNP: rs149656955
Type: single nucleotide variant
Location: chr5:14758507 (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 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-leu135 (accessed [today's date]).

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