Is ANKH p.Pro346Thr (c.1036C>A) pathogenic?

ANKH p.Pro346Thr (c.1036C>A) is classified Uncertain significance in ANKH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-11). AlphaMissense: likely benign (0.3317); Very rare (popmax 0.0011%, sas).

How common is ANKH p.Pro346Thr (c.1036C>A) in the general population?

ANKH p.Pro346Thr (c.1036C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ANKH p.Pro346Thr (c.1036C>A)?

AlphaMissense predicts likely benign (score 0.3317) — an in-silico prediction, not a clinical call.

ANKH p.Pro346Thr

c.1036C>A · VCV3572731

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3317 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3317	likely benign
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -11.68	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 160 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	25.7	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 0.0011% South Asian · 1/91,076 alleles

Overall 0.000137% 2/1,461,744 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,076
European (non-Finnish)	8.47e-05%	1,179,944

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.Pro346Thr
Coding: c.1036C>A
MANE Select: NM_054027
Type: single nucleotide variant
Location: chr5:14716811 (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

Similar variants

ANKH c.1142-4A>G Pathogenic/Likely pathogenic ★★ same type
ANKH c.96+5G>A Uncertain significance ★★ same type
ANKH c.*3752G>A Uncertain significance ★★ same type
ANKH p.Ala136Thr Uncertain significance ★★ ⚠ same type
ANKH p.Ala201Thr Uncertain significance ★★ ⚠ same type
ANKH p.Ala448Thr Uncertain significance ★★ same type
ANKH p.Arg453Gln Uncertain significance ★★ ⚠ same type
ANKH p.Asn306Asp Uncertain significance ★★ ⚠ same type

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-pro346thr (accessed [today's date]).

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