Is AKAP6 p.Ser1954Phe (c.5861C>T) pathogenic?

AKAP6 p.Ser1954Phe (c.5861C>T) is classified Uncertain significance in AKAP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-17). AlphaMissense: likely benign (0.1281); Ultra-rare (popmax 0.0501%, amr).

How common is AKAP6 p.Ser1954Phe (c.5861C>T) in the general population?

AKAP6 p.Ser1954Phe (c.5861C>T) is ultra-rare (popmax 0.0501%, amr) (gnomAD).

What do computational predictors say about AKAP6 p.Ser1954Phe (c.5861C>T)?

AlphaMissense predicts likely benign (score 0.1281) — an in-silico prediction, not a clinical call.

AKAP6 p.Ser1954Phe

c.5861C>T · rs201421428 · VCV2278248

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1281 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0501%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1281	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -7.97	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 0.85	GERP 3.2
Regional constraint	o/e 1.02	unconstrained · MANE · 279 kb · p 0.34 · regional, not allelic
Overall
CADD	19.19	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 0.0501% Admixed American · 30/59,934 alleles

Filtering AF 0.036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00316% 51/1,613,794 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0501%	1,998
Remaining individualsnot grpmax-eligible	0.0064%	15,625
European (non-Finnish)	0.00144%	69,406

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: AKAP6
Protein: p.Ser1954Phe
Coding: c.5861C>T
MANE Select: NM_004274
dbSNP: rs201421428
Type: single nucleotide variant
Location: chr14:32823674 (GRCh38)
Gene constraint: LOEUF 0.367 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 43.07

Full AKAP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AKAP6 p.Asn558Asp Benign ★★ same type
AKAP6 p.Glu2168= Benign ★★ same type
AKAP6 p.Glu892Lys Benign ★★ same type
AKAP6 p.Thr1516Ala Benign ★★ same type
AKAP6 p.Ala1022Val Uncertain significance ★ ⚠ same type
AKAP6 p.Ala123Asp Uncertain significance ★ ⚠ same type
AKAP6 p.Ala146Thr Uncertain significance ★ ⚠ same type
AKAP6 p.Ala1716Ser 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/akap6-p-ser1954phe (accessed [today's date]).

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