Is ANKS1A p.Ala554Asp (c.1661C>A) pathogenic?

ANKS1A p.Ala554Asp (c.1661C>A) is classified Uncertain significance in ANKS1A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.0848); Very rare (popmax 0.005%, amr).

How common is ANKS1A p.Ala554Asp (c.1661C>A) in the general population?

ANKS1A p.Ala554Asp (c.1661C>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about ANKS1A p.Ala554Asp (c.1661C>A)?

AlphaMissense predicts likely benign (score 0.0848) — an in-silico prediction, not a clinical call.

ANKS1A p.Ala554Asp

c.1661C>A · rs1204105508 · VCV3126959

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0848	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP -3.5, phastCons 0.5
Regional constraint	o/e 0.80	unconstrained · MANE · 105 kb · p 1.7e-11 · regional, not allelic
Overall
CADD	16.15	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 0.005% Admixed American · 3/60,016 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,613,878 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: ANKS1A
Protein: p.Ala554Asp
Coding: c.1661C>A
MANE Select: NM_015245
dbSNP: rs1204105508
Type: single nucleotide variant
Location: chr6:35017710 (GRCh38)
Gene constraint: LOEUF 0.549 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.78 · 3 PDB

Full ANKS1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKS1A p.Pro1089= Likely benign ★★ same type
ANKS1A p.Ala1061Val Uncertain significance ★ ⚠ same type
ANKS1A p.Ala1076Thr Uncertain significance ★ ⚠ same type
ANKS1A p.Ala1101Thr Uncertain significance ★ ⚠ same type
ANKS1A p.Ala268Thr Uncertain significance ★ ⚠ same type
ANKS1A p.Ala488Val Uncertain significance ★ ⚠ same type
ANKS1A p.Ala603Val Uncertain significance ★ ⚠ same type
ANKS1A p.Ala665Thr 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/anks1a-p-ala554asp (accessed [today's date]).

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