Is ACSL5 p.Pro99Thr (c.295C>A) pathogenic?

ACSL5 p.Pro99Thr (c.295C>A) is classified Uncertain significance in ACSL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-18). AlphaMissense: likely benign (0.1253); Ultra-rare (popmax 0.0579%, eas).

How common is ACSL5 p.Pro99Thr (c.295C>A) in the general population?

ACSL5 p.Pro99Thr (c.295C>A) is ultra-rare (popmax 0.0579%, eas) (gnomAD).

What do computational predictors say about ACSL5 p.Pro99Thr (c.295C>A)?

AlphaMissense predicts likely benign (score 0.1253) — an in-silico prediction, not a clinical call.

ACSL5 p.Pro99Thr

c.295C>A · rs531455951 · VCV2507514

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1253 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0579%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1253	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -9.62	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 3.4	GERP 2.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 32 kb · p 0.055 · regional, not allelic
Overall
CADD	23.7	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 0.0579% East Asian · 26/44,872 alleles

Filtering AF 0.0405% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0347%

Overall 0.00254% 41/1,613,696 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0579%	1,726
Remaining individualsnot grpmax-eligible	0.0128%	7,812
African / African-American	0.00666%	15,004
European (non-Finnish)	0.00017%	589,831

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.Pro99Thr
Coding: c.295C>A
MANE Select: NM_203379
dbSNP: rs531455951
Type: single nucleotide variant
Location: chr10:112404540 (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.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
ACSL5 c.-30+2164G>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-pro99thr (accessed [today's date]).

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