Is ACAD8 p.Arg102His (c.305G>A) pathogenic?

ACAD8 p.Arg102His (c.305G>A) is classified Uncertain significance in ACAD8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-29). AlphaMissense: ambiguous (0.5467); Very rare (popmax 0.00439%, sas); Associated with Inborn genetic diseases.

What condition is associated with ACAD8 p.Arg102His (c.305G>A)?

ACAD8 p.Arg102His (c.305G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ACAD8 p.Arg102His (c.305G>A) in the general population?

ACAD8 p.Arg102His (c.305G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about ACAD8 p.Arg102His (c.305G>A)?

AlphaMissense predicts ambiguous (score 0.5467) — an in-silico prediction, not a clinical call.

ACAD8 p.Arg102His

c.305G>A · rs143823240 · VCV2229936

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5467 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5467	ambiguous
REVEL	0.837	moderately pathogenic-leaning
SaProt	LLR -11.26	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 11 kb · p 0.076 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,088 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00212% 31/1,461,888 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,772
East Asian	0.00223%	44,876
European (non-Finnish)	0.00195%	51,306
Admixed American	0.00167%	60,018
Remaining individualsnot grpmax-eligible	0.0016%	62,510
African / African-American	0.00133%	75,032

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: ACAD8
Protein: p.Arg102His
Coding: c.305G>A
MANE Select: NM_014384
dbSNP: rs143823240
Type: single nucleotide variant
Location: chr11:134257182 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 94.19 · 1 PDB
Residue 102: an α-helix

Full ACAD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACAD8 p.Arg102Leu Uncertain significance ★ ⚠ same residue
ACAD8 p.Arg102Pro Uncertain significance ★ ⚠ same residue
ACAD8 p.Arg206Ter Pathogenic ★★ same condition
ACAD8 c.841+6A>C Uncertain significance ★★ same condition
ACAD8 p.Ala113Thr Uncertain significance ★★ ⚠ same condition
ACAD8 p.Arg244Gly Uncertain significance ★★ ⚠ same condition
ACAD8 p.Asp346Asn Uncertain significance ★★ ⚠ same condition
ACAD8 p.Glu44Lys Uncertain significance ★★ ⚠ same condition

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/acad8-p-arg102his (accessed [today's date]).

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