Is ANKRD33B p.Arg486Cys (c.1456C>T) pathogenic?

ANKRD33B p.Arg486Cys (c.1456C>T) is classified Uncertain significance in ANKRD33B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely benign (0.1839); Ultra-rare (popmax 0.0421%, eas).

How common is ANKRD33B p.Arg486Cys (c.1456C>T) in the general population?

ANKRD33B p.Arg486Cys (c.1456C>T) is ultra-rare (popmax 0.0421%, eas) (gnomAD).

What do computational predictors say about ANKRD33B p.Arg486Cys (c.1456C>T)?

AlphaMissense predicts likely benign (score 0.1839) — an in-silico prediction, not a clinical call.

ANKRD33B p.Arg486Cys

c.1456C>T · VCV4106585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1839 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0421%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1839	likely benign
REVEL	0.222	benign-leaning
SaProt	LLR -9.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	donor gain · deltas
Pangolin	Δ0.27	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.7	GERP -1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 85 kb · p 0.32 · regional, not allelic
Overall
CADD	25.5	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 0.0421% East Asian · 17/40,338 alleles

Filtering AF 0.0269% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.022%

Overall 0.00118% 18/1,526,916 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0421%	2,373
European (non-Finnish)	8.76e-05%	1,141,605

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.Arg486Cys
Coding: c.1456C>T
MANE Select: NM_001164440
Type: single nucleotide variant
Location: chr5:10650084 (GRCh38)
Gene constraint: LOEUF 0.682 · pLI 0.70 (gnomAD)
Structure: AlphaFold pLDDT 67.74
Residue 486: the 'disordered' region

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

Similar variants

ANKRD33B p.Arg486His Uncertain significance ★ ⚠ same residue
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

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-arg486cys (accessed [today's date]).

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