Is ANKH p.Pro5Leu (c.14C>T) pathogenic?

ANKH p.Pro5Leu (c.14C>T) is classified Likely pathogenic in ANKH (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-03). AlphaMissense: likely pathogenic (0.5918); Very rare (popmax 8.48e-05%, nfe); Associated with chondrocalcinosis 2.

What condition is associated with ANKH p.Pro5Leu (c.14C>T)?

ANKH p.Pro5Leu (c.14C>T) is associated with chondrocalcinosis 2 (ClinVar).

How common is ANKH p.Pro5Leu (c.14C>T) in the general population?

ANKH p.Pro5Leu (c.14C>T) is very rare (popmax 8.48e-05%, nfe) (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.Pro5Leu (c.14C>T)?

AlphaMissense predicts likely pathogenic (score 0.5918) — an in-silico prediction, not a clinical call.

ANKH p.Pro5Leu

c.14C>T · rs121908409 · VCV5198

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5918 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

chondrocalcinosis 2

Computational evidence

Protein change
AlphaMissense	0.5918	likely pathogenic ✓ concordant with ClinVar
REVEL	0.602	indeterminate
SaProt	LLR -8.45	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 160 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	31.0	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 8.48e-05% European (non-Finnish) · 1/1,179,154 alleles

Overall 6.85e-05% 1/1,460,444 alleles · very rare

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.Pro5Leu
Coding: c.14C>T
MANE Select: NM_054027
dbSNP: rs121908409
Type: single nucleotide variant
Location: chr5:14871434 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.57
Residue 5: a UniProt-annotated variant site (in ccal2)

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

For Familial calcium pyrophosphate deposition (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult

Similar variants

ANKH p.Pro5Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
ANKH p.Pro5Thr Pathogenic/Likely pathogenic ⚠ same residue
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.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-pro5leu (accessed [today's date]).

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