Is ACTB p.Arg196Leu (c.587G>T) pathogenic?

ACTB p.Arg196Leu (c.587G>T) is classified Likely pathogenic in ACTB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-01). AlphaMissense: likely pathogenic (0.9938); Absent from gnomAD v4.1; Associated with aminoacylase 1 deficiency.

What condition is associated with ACTB p.Arg196Leu (c.587G>T)?

ACTB p.Arg196Leu (c.587G>T) is associated with aminoacylase 1 deficiency, Baraitser-Winter syndrome 1 (ClinVar).

How common is ACTB p.Arg196Leu (c.587G>T) in the general population?

ACTB p.Arg196Leu (c.587G>T) is absent from gnomAD v4.1 (gnomAD).

How is Aminoacylase 1 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ACTB p.Arg196Leu (c.587G>T)?

AlphaMissense predicts likely pathogenic (score 0.9938) — an in-silico prediction, not a clinical call.

ACTB p.Arg196Leu

c.587G>T · rs281875334 · VCV1177326

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9938 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

aminoacylase 1 deficiency

Computational evidence

Protein change
AlphaMissense	0.9938	likely pathogenic ✓ concordant with ClinVar
REVEL	0.884	moderately pathogenic-leaning
SaProt	LLR -12.85	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 2.2	GERP -0.57, phastCons 0.98
Regional constraint	o/e 0.11	constrained · MANE · 1,149 bp · p 1.6e-51 · regional, not allelic
Overall
CADD	33.0	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

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: ACTB
Protein: p.Arg196Leu
Coding: c.587G>T
MANE Select: NM_001101
dbSNP: rs281875334
Type: single nucleotide variant
Location: chr7:5528496 (GRCh38)
Gene constraint: LOEUF 0.193 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 95.31 · 93 PDB
Residue 196: a UniProt-annotated variant site (in brws1); an α-helix

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

Disease context

aminoacylase 1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Baraitser-Winter syndrome 1

For Aminoacylase 1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

ACTB p.Arg196Cys Pathogenic ★★ same residue
ACTB p.Arg196His Pathogenic ★★ same residue
ACTB p.Arg196= Likely benign ★★ same residue
ACTB p.Arg196Ser Pathogenic same residue
ACTB p.Arg196Gly Pathogenic ★ same residue
ACTB p.Ala22Thr Likely pathogenic ★★ same condition
ACTB p.Ala7Thr Likely pathogenic ★★ same condition
ACTB p.Arg147Cys Pathogenic ★★ 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/actb-p-arg196leu (accessed [today's date]).

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