Is ANKRD33B p.Glu466Lys (c.1396G>A) pathogenic?

ANKRD33B p.Glu466Lys (c.1396G>A) is classified Uncertain significance in ANKRD33B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). AlphaMissense: ambiguous (0.3612); Very rare (popmax 0.00402%, nfe).

How common is ANKRD33B p.Glu466Lys (c.1396G>A) in the general population?

ANKRD33B p.Glu466Lys (c.1396G>A) is very rare (popmax 0.00402%, nfe) (gnomAD).

What do computational predictors say about ANKRD33B p.Glu466Lys (c.1396G>A)?

AlphaMissense predicts ambiguous (score 0.3612) — an in-silico prediction, not a clinical call.

ANKRD33B p.Glu466Lys

c.1396G>A · rs952656310 · VCV2394427

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3612 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3612	ambiguous
REVEL	0.138	moderately benign-leaning
SaProt	LLR -6.41	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 85 kb · p 0.32 · regional, not allelic
Overall
CADD	28.4	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 0.00402% European (non-Finnish) · 46/1,144,594 alleles

Filtering AF 0.00308% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.0032% 49/1,533,068 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00402%	24,882
Remaining individualsnot grpmax-eligible	0.00335%	29,836
Admixed American	0.00197%	50,790

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: ANKRD33B
Protein: p.Glu466Lys
Coding: c.1396G>A
MANE Select: NM_001164440
dbSNP: rs952656310
Type: single nucleotide variant
Location: chr5:10650024 (GRCh38)
Gene constraint: LOEUF 0.682 · pLI 0.70 (gnomAD)
Structure: AlphaFold pLDDT 67.74
Residue 466: the 'disordered' region

Full ANKRD33B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRD33B p.Asp301Asn Uncertain significance ★★ ⚠ same type
ANKRD33B p.Ala158Pro Uncertain significance ★ ⚠ same type
ANKRD33B p.Ala168Val Uncertain significance ★ ⚠ same type
ANKRD33B p.Ala214Val Uncertain significance ★ ⚠ same type
ANKRD33B p.Ala274Thr Uncertain significance ★ ⚠ same type
ANKRD33B p.Ala319Val Uncertain significance ★ ⚠ same type
ANKRD33B p.Ala348Val Uncertain significance ★ ⚠ same type
ANKRD33B p.Ala350Val 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/ankrd33b-p-glu466lys (accessed [today's date]).

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