Is ANKH p.Leu415Val (c.1243C>G) pathogenic?

ANKH p.Leu415Val (c.1243C>G) is classified Uncertain significance in ANKH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.6749); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with ANKH p.Leu415Val (c.1243C>G)?

ANKH p.Leu415Val (c.1243C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ANKH p.Leu415Val (c.1243C>G) in the general population?

ANKH p.Leu415Val (c.1243C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ANKH p.Leu415Val (c.1243C>G)?

AlphaMissense predicts likely pathogenic (score 0.6749) — an in-silico prediction, not a clinical call.

ANKH p.Leu415Val

c.1243C>G · VCV4577504

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6749	likely pathogenic
REVEL	0.815	moderately pathogenic-leaning
SaProt	LLR -8.48	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 160 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	25.6	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 0.00133% African / African-American · 1/74,956 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,136 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,956
European (non-Finnish)	0.000254%	393,352

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.Leu415Val
Coding: c.1243C>G
MANE Select: NM_054027
Type: single nucleotide variant
Location: chr5:14713566 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ANKH p.Ala136Thr Uncertain significance ★★ ⚠ same condition
ANKH p.Arg453Gln Uncertain significance ★★ ⚠ same condition
ANKH p.Asn306Asp Uncertain significance ★★ ⚠ same condition
ANKH p.Asn347Ser Uncertain significance ★★ ⚠ same condition
ANKH p.Asp218Asn Uncertain significance ★★ ⚠ same condition
ANKH p.Glu47Lys Uncertain significance ★★ ⚠ same condition
ANKH p.Glu480Val Uncertain significance ★★ ⚠ same condition
ANKH p.Glu486Lys Uncertain significance ★★ ⚠ 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-leu415val (accessed [today's date]).

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