Is ANKH p.Met48Thr (c.143T>C) pathogenic?

ANKH p.Met48Thr (c.143T>C) is classified Pathogenic in ANKH (ClinVar, No assertion criteria, 1 submitter; last evaluated 2002-10-01). AlphaMissense: ambiguous (0.4287); Absent from gnomAD v4.1; Associated with chondrocalcinosis 2.

What condition is associated with ANKH p.Met48Thr (c.143T>C)?

ANKH p.Met48Thr (c.143T>C) is associated with chondrocalcinosis 2 (ClinVar).

How common is ANKH p.Met48Thr (c.143T>C) in the general population?

ANKH p.Met48Thr (c.143T>C) is absent from gnomAD v4.1 (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.Met48Thr (c.143T>C)?

AlphaMissense predicts ambiguous (score 0.4287) — an in-silico prediction, not a clinical call.

ANKH p.Met48Thr

c.143T>C · rs121908407 · VCV5195

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4287 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

chondrocalcinosis 2

Computational evidence

Protein change
AlphaMissense	0.4287	ambiguous
REVEL	0.75	pathogenic-leaning
SaProt	LLR -4.44	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 160 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	23.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ANKH
Protein: p.Met48Thr
Coding: c.143T>C
MANE Select: NM_054027
dbSNP: rs121908407
Type: single nucleotide variant
Location: chr5:14769145 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.57
Residue 48: 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.Met48Lys Uncertain significance ★ ⚠ same residue
ANKH p.Met48Val Uncertain significance ★ 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-met48thr (accessed [today's date]).

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