Is ANKH p.Arg453Trp (c.1357C>T) pathogenic?

ANKH p.Arg453Trp (c.1357C>T) is classified Conflicting classifications of pathogenicity in ANKH (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-02). AlphaMissense: likely benign (0.2035); Rare (popmax 0.313%, mid); Associated with chondrocalcinosis 2.

What condition is associated with ANKH p.Arg453Trp (c.1357C>T)?

ANKH p.Arg453Trp (c.1357C>T) is associated with chondrocalcinosis 2, craniometaphyseal dysplasia, autosomal dominant (ClinVar).

How common is ANKH p.Arg453Trp (c.1357C>T) in the general population?

ANKH p.Arg453Trp (c.1357C>T) is rare (popmax 0.313%, mid) (gnomAD).

How is Familial calcium pyrophosphate deposition inherited?

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

What do computational predictors say about ANKH p.Arg453Trp (c.1357C>T)?

AlphaMissense predicts likely benign (score 0.2035) — an in-silico prediction, not a clinical call.

ANKH p.Arg453Trp

c.1357C>T · rs761349696 · VCV905793

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2035 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.313%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

chondrocalcinosis 2

Computational evidence

Protein change
AlphaMissense	0.2035	likely benign
REVEL	0.783	moderately pathogenic-leaning
SaProt	LLR -6.97	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.59, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 160 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.313% Middle Eastern · 19/6,066 alleles

Filtering AF 0.205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.171%

Overall 0.00255% 41/1,609,410 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.313%	319
East Asian	0.00224%	44,740
European (non-Finnish)	0.00161%	62,020
African / African-American	0.00134%	74,866
South Asian	0.00111%	89,892

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.Arg453Trp
Coding: c.1357C>T
MANE Select: NM_054027
dbSNP: rs761349696
Type: single nucleotide variant
Location: chr5:14712882 (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.Arg453Gln 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-arg453trp (accessed [today's date]).

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