Is ANKH p.Ile216Val (c.646A>G) pathogenic?

ANKH p.Ile216Val (c.646A>G) is classified Uncertain significance in ANKH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-15). AlphaMissense: likely benign (0.0897); Very rare (popmax 0.000424%, nfe).

How common is ANKH p.Ile216Val (c.646A>G) in the general population?

ANKH p.Ile216Val (c.646A>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about ANKH p.Ile216Val (c.646A>G)?

AlphaMissense predicts likely benign (score 0.0897) — an in-silico prediction, not a clinical call.

ANKH p.Ile216Val

c.646A>G · rs749003605 · VCV2974551

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0897 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0897	likely benign
REVEL	0.341	indeterminate
SaProt	LLR -6.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 160 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	18.62	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,048 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,890 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.Ile216Val
Coding: c.646A>G
MANE Select: NM_054027
dbSNP: rs749003605
Type: single nucleotide variant
Location: chr5:14751110 (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-ile216val (accessed [today's date]).

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