Is ANKIB1 p.Cys519Trp (c.1557T>G) pathogenic?

ANKIB1 p.Cys519Trp (c.1557T>G) is classified Uncertain significance in ANKIB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-29). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1.

How common is ANKIB1 p.Cys519Trp (c.1557T>G) in the general population?

ANKIB1 p.Cys519Trp (c.1557T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ANKIB1 p.Cys519Trp (c.1557T>G)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

ANKIB1 p.Cys519Trp

c.1557T>G · VCV4099098

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 2% in ANKIB1
REVEL	0.89	moderately pathogenic-leaning
SaProt	LLR -16.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 3.2, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 85 kb · p 3.4e-20 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ANKIB1
Protein: p.Cys519Trp
Coding: c.1557T>G
MANE Select: NM_019004
Type: single nucleotide variant
Location: chr7:92371547 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.34 (gnomAD)
Structure: AlphaFold pLDDT 66.52
Residue 519: a binding site; the 'triad supradomain' region

Full ANKIB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKIB1 c.-605T>C Benign/Likely benign ★★ same type
ANKIB1 p.Ala1062Val Uncertain significance ★ ⚠ same type
ANKIB1 p.Ala126Thr Uncertain significance ★ ⚠ same type
ANKIB1 p.Ala218Thr Uncertain significance ★ ⚠ same type
ANKIB1 p.Ala257Gly Uncertain significance ★ ⚠ same type
ANKIB1 p.Ala986Val Uncertain significance ★ ⚠ same type
ANKIB1 p.Arg102Cys Uncertain significance ★ same type
ANKIB1 p.Arg102Leu 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/ankib1-p-cys519trp (accessed [today's date]).

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