Is ACACA p.Gln105Leu (c.314A>T) pathogenic?

ACACA p.Gln105Leu (c.314A>T) is classified Conflicting classifications of pathogenicity in ACACA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-19). AlphaMissense: likely benign (0.1211); Rare (popmax 0.737%, afr).

How common is ACACA p.Gln105Leu (c.314A>T) in the general population?

ACACA p.Gln105Leu (c.314A>T) is rare (popmax 0.737%, afr) (gnomAD).

What do computational predictors say about ACACA p.Gln105Leu (c.314A>T)?

AlphaMissense predicts likely benign (score 0.1211) — an in-silico prediction, not a clinical call.

ACACA p.Gln105Leu

c.314A>T · rs61743749 · VCV3022984

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1211 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.737%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1211	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -5.92	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 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 121 kb · p 0.52 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM Q68L vs ClinVar Q105L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.737% African / African-American · 553/75,064 alleles

Filtering AF 0.686% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.666%

Overall 0.0366% 591/1,614,224 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.737%	136
Remaining individualsnot grpmax-eligible	0.0384%	2,604
Admixed American	0.0183%	5,457
South Asian	0.0011%	91,088
European (non-Finnish)	0.000169%	590,023

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
Protein: p.Gln105Leu
Coding: c.314A>T
MANE Select: NM_198834
dbSNP: rs61743749
Type: single nucleotide variant
Location: chr17:37330197 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 105: an α-helix

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

Similar variants

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ACACA p.Arg745Trp Uncertain significance ★★ ⚠ same type
ACACA p.Asn1903Ser Uncertain significance ★★ ⚠ same type
ACACA p.Asn728Ser Uncertain significance ★★ ⚠ same type
ACACA p.Asn950Ser Uncertain significance ★★ ⚠ same type
ACACA p.Asp2228Asn 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/acaca-p-gln105leu (accessed [today's date]).

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