Is ANKH p.Glu489fs (c.1466_1467del) pathogenic?

ANKH p.Glu489fs (c.14661467del) is classified Uncertain significance in ANKH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). Very rare (popmax 0.004%, afr).

How common is ANKH p.Glu489fs (c.1466_1467del) in the general population?

ANKH p.Glu489fs (c.1466_1467del) is very rare (popmax 0.004%, afr) (gnomAD).

ANKH p.Glu489fs

c.1466_1467del · VCV3629114

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon in the last exon (12 of 12) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.9	GERP 1.5, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,926 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000558% 9/1,613,900 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,975
East Asian	0.00223%	44,882
European (non-Finnish)	0.000424%	235,979

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.Glu489fs
Coding: c.1466_1467del
MANE Select: NM_054027
Type: Microsatellite
Location: chr5:14711209 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.57
Residue 489: the 'disordered' region

Full ANKH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKH p.Glu489_Glu490insTer Uncertain significance ★ same residue
ANKH p.Glu489Gly Uncertain significance ★ ⚠ same residue
ANKH p.Phe377del Pathogenic ★★ same type
ANKH c.-80GTCGCCCC[1] Benign ★★ same type
ANKH c.-291CCG[6] Uncertain significance ★ same type
ANKH p.Lys458del Uncertain significance ★ same type
ANKH c.1141+190TATT[5] Benign ★ same type
ANKH c.1141+190TATT[8] Likely benign ★ 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-glu489fs (accessed [today's date]).

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