Is ACAA1 p.Ser17Ala (c.49T>G) pathogenic?

ACAA1 p.Ser17Ala (c.49T>G) is classified Uncertain significance in ACAA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.0599); Ultra-rare (popmax 0.0247%, sas).

How common is ACAA1 p.Ser17Ala (c.49T>G) in the general population?

ACAA1 p.Ser17Ala (c.49T>G) is ultra-rare (popmax 0.0247%, sas) (gnomAD).

What do computational predictors say about ACAA1 p.Ser17Ala (c.49T>G)?

AlphaMissense predicts likely benign (score 0.0599) — an in-silico prediction, not a clinical call.

ACAA1 p.Ser17Ala

c.49T>G · VCV4195678

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0599 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0247%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0599	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -6.07	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 0.55	GERP -3.1
Regional constraint	o/e 0.91	unconstrained · MANE · 14 kb · p 0.034 · regional, not allelic
Overall
CADD	4.077	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 0.0247% South Asian · 21/84,976 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00147% 23/1,562,362 alleles · ultra-rare exomes 21/1,410,140 · genomes 2/152,222 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0247%	4,046
Remaining individualsnot grpmax-eligible	0.00165%	60,506
European (non-Finnish)	8.65e-05%	1,155,803

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: ACAA1
Protein: p.Ser17Ala
Coding: c.49T>G
MANE Select: NM_001607
Type: single nucleotide variant
Location: chr3:38136987 (GRCh38)
Gene constraint: LOEUF 1.199 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.93 · 2 PDB
Residue 17: the 'pts2-type peroxisomal targeting signal' region

Full ACAA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACAA1 p.Ser17Phe Uncertain significance ★ ⚠ same residue
ACAA1 p.Glu172Asp Benign ★★ same type
ACAA1 p.Ala131Ser Uncertain significance ★ ⚠ same type
ACAA1 p.Ala24Val Uncertain significance ★ ⚠ same type
ACAA1 p.Ala324Gly Uncertain significance ★ ⚠ same type
ACAA1 p.Ala33Thr Uncertain significance ★ ⚠ same type
ACAA1 p.Ala416Thr Uncertain significance ★ ⚠ same type
ACAA1 p.Arg167Cys 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/acaa1-p-ser17ala (accessed [today's date]).

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