Is ACTR5 p.Pro49Arg (c.146C>G) pathogenic?

ACTR5 p.Pro49Arg (c.146C>G) is classified Uncertain significance in ACTR5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-10). AlphaMissense: likely benign (0.0963); Very rare (popmax 0.00145%, afr).

How common is ACTR5 p.Pro49Arg (c.146C>G) in the general population?

ACTR5 p.Pro49Arg (c.146C>G) is very rare (popmax 0.00145%, afr) (gnomAD).

What do computational predictors say about ACTR5 p.Pro49Arg (c.146C>G)?

AlphaMissense predicts likely benign (score 0.0963) — an in-silico prediction, not a clinical call.

ACTR5 p.Pro49Arg

c.146C>G · rs1568632988 · VCV2242237

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0963 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00145%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0963	likely benign
REVEL	0.36	indeterminate
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.3, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 23 kb · p 0.57 · regional, not allelic
Overall
CADD	23.5	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 0.00145% African / African-American · 1/69,002 alleles

Overall 0.000657% 1/152,190 alleles · very rare

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: ACTR5
Protein: p.Pro49Arg
Coding: c.146C>G
MANE Select: NM_024855
dbSNP: rs1568632988
Type: single nucleotide variant
Location: chr20:38748624 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.75 · 6 PDB

Full ACTR5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTR5 p.Pro49Ser Uncertain significance ★ ⚠ same residue
ACTR5 p.Ala11Thr Uncertain significance ★ ⚠ same type
ACTR5 p.Ala13Val Uncertain significance ★ ⚠ same type
ACTR5 p.Ala14Thr Uncertain significance ★ ⚠ same type
ACTR5 p.Ala235Thr Uncertain significance ★ ⚠ same type
ACTR5 p.Ala253Thr Uncertain significance ★ ⚠ same type
ACTR5 p.Ala371Val Uncertain significance ★ ⚠ same type
ACTR5 p.Ala541Gly 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/actr5-p-pro49arg (accessed [today's date]).

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