Is AKAP8L p.Ser93Phe (c.278C>T) pathogenic?

AKAP8L p.Ser93Phe (c.278C>T) is classified Uncertain significance in AKAP8L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: ambiguous (0.4182); Ultra-rare (popmax 0.0822%, mid).

How common is AKAP8L p.Ser93Phe (c.278C>T) in the general population?

AKAP8L p.Ser93Phe (c.278C>T) is ultra-rare (popmax 0.0822%, mid) (gnomAD).

What do computational predictors say about AKAP8L p.Ser93Phe (c.278C>T)?

AlphaMissense predicts ambiguous (score 0.4182) — an in-silico prediction, not a clinical call.

AKAP8L p.Ser93Phe

c.278C>T · rs372294703 · VCV2589489

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4182 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0822%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4182	ambiguous
REVEL	0.184	benign-leaning
SaProt	LLR -11.83	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 22 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0822% Middle Eastern · 5/6,082 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00979% 158/1,613,828 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0822%	1,216
Remaining individualsnot grpmax-eligible	0.0208%	4,805
European (non-Finnish)	0.0114%	8,740
African / African-American	0.00401%	24,963
Admixed American	0.00333%	30,000

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: AKAP8L
Protein: p.Ser93Phe
Coding: c.278C>T
MANE Select: NM_014371
dbSNP: rs372294703
Type: single nucleotide variant
Location: chr19:15403559 (GRCh38)
Gene constraint: LOEUF 0.592 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 55.46
Residue 93: the 'sufficient for activation of cte-mediated expression' region

Full AKAP8L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AKAP8L p.Cys128= Benign ★★ same type
AKAP8L p.Ala321Ser Uncertain significance ★ ⚠ same type
AKAP8L p.Ala351Pro Conflicting classifications of pathogenicity ★ ⚠ same type
AKAP8L p.Ala405Thr Uncertain significance ★ ⚠ same type
AKAP8L p.Ala482Thr Uncertain significance ★ ⚠ same type
AKAP8L p.Ala526Thr Uncertain significance ★ ⚠ same type
AKAP8L p.Ala562Thr Uncertain significance ★ ⚠ same type
AKAP8L p.Ala566Thr 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/akap8l-p-ser93phe (accessed [today's date]).

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