Is ACSL5 p.Arg540His (c.1619G>A) pathogenic?

ACSL5 p.Arg540His (c.1619G>A) is classified Uncertain significance in ACSL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-23). AlphaMissense: likely pathogenic (0.9753); Very rare (popmax 0.00475%, nfe).

How common is ACSL5 p.Arg540His (c.1619G>A) in the general population?

ACSL5 p.Arg540His (c.1619G>A) is very rare (popmax 0.00475%, nfe) (gnomAD).

What do computational predictors say about ACSL5 p.Arg540His (c.1619G>A)?

AlphaMissense predicts likely pathogenic (score 0.9753) — an in-silico prediction, not a clinical call.

ACSL5 p.Arg540His

c.1619G>A · VCV3825348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00475%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9753	likely pathogenic · top 6% in ACSL5
REVEL	0.651	pathogenic-leaning
SaProt	LLR -15.49	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 32 kb · p 0.055 · regional, not allelic
Overall
CADD	33.0	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 0.00475% European (non-Finnish) · 56/1,179,220 alleles

Filtering AF 0.00375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00337%

Overall 0.00366% 59/1,612,264 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00475%	21,058
East Asian	0.00224%	44,736
Admixed American	0.00167%	59,760
Remaining individualsnot grpmax-eligible	0.0016%	62,410

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: ACSL5
Protein: p.Arg540His
Coding: c.1619G>A
MANE Select: NM_203379
Type: single nucleotide variant
Location: chr10:112425363 (GRCh38)
Gene constraint: LOEUF 0.702 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.55

Full ACSL5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACSL5 p.Arg540Cys Uncertain significance ★ ⚠ same residue
ACSL5 p.Leu377= Benign ★★ same type
ACSL5 p.Pro40His Benign ★★ ⚠ same type
ACSL5 p.Thr486Ala Benign ★★ same type
ACSL5 c.-30+2050C>G Uncertain significance ★ same type
ACSL5 c.-30+2076C>A Uncertain significance ★ same type
ACSL5 c.-30+2100G>C Uncertain significance ★ same type
ACSL5 c.-30+2128C>T 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/acsl5-p-arg540his (accessed [today's date]).

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