Is ACACA p.Glu606Lys (c.1816G>A) pathogenic?

ACACA p.Glu606Lys (c.1816G>A) is classified Uncertain significance in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.8207); Absent from gnomAD v4.1; Associated with cardiac anomalies - developmental delay - facial dysmorphism syndrome.

What condition is associated with ACACA p.Glu606Lys (c.1816G>A)?

ACACA p.Glu606Lys (c.1816G>A) is associated with cardiac anomalies - developmental delay - facial dysmorphism syndrome (ClinVar).

How common is ACACA p.Glu606Lys (c.1816G>A) in the general population?

ACACA p.Glu606Lys (c.1816G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACACA p.Glu606Lys (c.1816G>A)?

AlphaMissense predicts likely pathogenic (score 0.8207) — an in-silico prediction, not a clinical call.

ACACA p.Glu606Lys

c.1816G>A · VCV4278454

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8207 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiac anomalies - developmental delay - facial dysmorphism syndrome

Computational evidence

Protein change
AlphaMissense	0.8207	likely pathogenic
REVEL	0.692	pathogenic-leaning
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 5,358 bp · p 9.3e-19 · regional, not allelic
Overall
CADD	29.8	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 E569K vs ClinVar E606K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACACA
Protein: p.Glu606Lys
Coding: c.1816G>A
MANE Select: NM_198834
Type: single nucleotide variant
Location: chr17:37257713 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 606: the biotin carboxylation domain

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

Disease context

cardiac anomalies - developmental delay - facial dysmorphism syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACACA p.Ala2308Val Uncertain significance ★★ ⚠ same type
ACACA p.Arg1206His Uncertain significance ★★ ⚠ same type
ACACA p.Arg2198Gln Uncertain significance ★★ ⚠ same type
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-glu606lys (accessed [today's date]).

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