Is AKAP1 p.Ala557Ser (c.1669G>T) pathogenic?

AKAP1 p.Ala557Ser (c.1669G>T) is classified Uncertain significance in AKAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-13). AlphaMissense: likely benign (0.0752); Ultra-rare (popmax 0.0316%, nfe).

How common is AKAP1 p.Ala557Ser (c.1669G>T) in the general population?

AKAP1 p.Ala557Ser (c.1669G>T) is ultra-rare (popmax 0.0316%, nfe) (gnomAD).

What do computational predictors say about AKAP1 p.Ala557Ser (c.1669G>T)?

AlphaMissense predicts likely benign (score 0.0752) — an in-silico prediction, not a clinical call.

AKAP1 p.Ala557Ser

c.1669G>T · rs141130461 · VCV2211412

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0752 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0316%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0752	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -5.12	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 0.82	GERP -3.5, phastCons 0.99
Regional constraint	o/e 0.81	unconstrained · MANE · 14 kb · p 5.3e-08 · regional, not allelic
Overall
CADD	11.65	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 0.0316% European (non-Finnish) · 373/1,179,720 alleles

Filtering AF 0.0289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0279%

Overall 0.0285% 460/1,613,742 alleles · ultra-rare exomes 408/1,461,408 · genomes 52/152,334 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.64%	61
Ashkenazi Jewishnot grpmax-eligible	0.145%	688
European (non-Finnish)grpmax	0.0316%	3,163
Remaining individualsnot grpmax-eligible	0.024%	4,165
Admixed American	0.0183%	5,455
African / African-American	0.00266%	37,524
Finnishnot grpmax-eligible	0.00156%	64,004

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: AKAP1
Protein: p.Ala557Ser
Coding: c.1669G>T
MANE Select: NM_003488
dbSNP: rs141130461
Type: single nucleotide variant
Location: chr17:57107133 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.67 (gnomAD)
Structure: AlphaFold pLDDT 57.02

Full AKAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AKAP1 c.1976-6A>G Benign ★★ same type
AKAP1 p.Ala218Thr Benign ★★ same type
AKAP1 p.Gly323Ser Benign ★★ same type
AKAP1 p.Pro475= Benign ★★ same type
AKAP1 p.Pro818= Benign ★★ same type
AKAP1 p.Ser330Gly Benign ★★ same type
AKAP1 p.Ser388= Benign ★★ same type
AKAP1 p.Thr521Ile 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/akap1-p-ala557ser (accessed [today's date]).

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