Is ACACA c.3474+2TA[13] pathogenic?

ACACA c.3474+2TA[13] is classified Benign in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-28). Common (popmax 26.9%, eas) — too common for a highly-penetrant pathogenic allele.

ACACA c.3474+2TA[13]

Q: How common is ACACA c.3474+2TA[13] in the general population?

ACACA c.3474+2TA[13] is common (popmax 26.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

VCV4684206

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Common

common (popmax 26.9%, eas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function in a LoF-intolerant gene
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3.7	GERP -2.4
Non-coding constraint	Z 0.41	1 kb window · o/e 0.96 · regional · uncalibrated
Overall
CADD	0.387	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(TA)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 26.9% East Asian · 8,257/30,728 alleles

Filtering AF 26.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 26.2%

Overall 10.7% 96,522/904,530 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	26.9%	4
South Asian	14.2%	7
Finnishnot grpmax-eligible	13.2%	8
Admixed American	11.8%	8
African / African-American	11.1%	9
Remaining individualsnot grpmax-eligible	9.76%	10
European (non-Finnish)	9.51%	11
Middle Eastern	9.38%	11
Ashkenazi Jewishnot grpmax-eligible	7.05%	14
Amishnot grpmax-eligible	5.77%	17

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: ACACA
Coding: c.3474+2TA[13]
MANE Select: NM_198834
Type: Microsatellite
Location: chr17:37224966 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB

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

Similar variants

ACACA c.3474+2TA[14] Uncertain significance ★ same type
ACACA c.3474+2TA[11] Benign ★ same type
ACACA c.3474+2TA[8] Likely benign ★ same type
ACACA c.5945-22TTTC[2] 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/acaca-c-3474-plus-2ta-13 (accessed [today's date]).

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