Is ABCA9 p.Ser699Phe (c.2096C>T) pathogenic?

ABCA9 p.Ser699Phe (c.2096C>T) is classified Uncertain significance in ABCA9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). AlphaMissense: likely pathogenic (0.8348); Very rare (popmax 0.00669%, eas).

How common is ABCA9 p.Ser699Phe (c.2096C>T) in the general population?

ABCA9 p.Ser699Phe (c.2096C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about ABCA9 p.Ser699Phe (c.2096C>T)?

AlphaMissense predicts likely pathogenic (score 0.8348) — an in-silico prediction, not a clinical call.

ABCA9 p.Ser699Phe

c.2096C>T · VCV3528598

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8348 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8348	likely pathogenic · top 6% in ABCA9
REVEL	0.606	indeterminate
SaProt	LLR -15.69	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 75 kb · p 0.014 · regional, not allelic
Overall
CADD	24.3	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

Grpmax group 0.00669% East Asian · 3/44,876 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000248% 4/1,613,772 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,959
South Asian	0.0011%	91,090

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: ABCA9
Protein: p.Ser699Phe
Coding: c.2096C>T
MANE Select: NM_080283
Type: single nucleotide variant
Location: chr17:69026422 (GRCh38)
Gene constraint: LOEUF 1.006 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.22
Residue 699: the abc transporter 1 domain

Full ABCA9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA9 p.Tyr1123= Likely benign ★★ same type
ABCA9 p.Ala1071Val Uncertain significance ★ ⚠ same type
ABCA9 p.Ala1153Thr Uncertain significance ★ ⚠ same type
ABCA9 p.Ala1196Thr Uncertain significance ★ ⚠ same type
ABCA9 p.Ala125Thr Uncertain significance ★ ⚠ same type
ABCA9 p.Ala1285Thr Uncertain significance ★ ⚠ same type
ABCA9 p.Ala1407Val Uncertain significance ★ ⚠ same type
ABCA9 p.Ala1492Pro 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/abca9-p-ser699phe (accessed [today's date]).

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