Is ACVR2A p.Pro49Leu (c.146C>T) pathogenic?

ACVR2A p.Pro49Leu (c.146C>T) is classified Uncertain significance in ACVR2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely benign (0.0886); Very rare (popmax 0.00439%, sas).

How common is ACVR2A p.Pro49Leu (c.146C>T) in the general population?

ACVR2A p.Pro49Leu (c.146C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about ACVR2A p.Pro49Leu (c.146C>T)?

AlphaMissense predicts likely benign (score 0.0886) — an in-silico prediction, not a clinical call.

ACVR2A p.Pro49Leu

c.146C>T · rs776542712 · VCV3143088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0886	likely benign
REVEL	0.397	indeterminate
SaProt	LLR -5.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP -0.52, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 55 kb · p 3.8e-05 · regional, not allelic
Overall
CADD	21.7	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 0.00439% South Asian · 4/91,062 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00112% 18/1,613,718 alleles · very rare exomes 16/1,461,670 · genomes 2/152,048 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,766
African / African-American	0.00401%	24,952
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)	0.000763%	131,102

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: ACVR2A
Protein: p.Pro49Leu
Coding: c.146C>T
MANE Select: NM_001616
dbSNP: rs776542712
Type: single nucleotide variant
Location: chr2:147896391 (GRCh38)
Gene constraint: LOEUF 0.222 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.20 · 5 PDB
Residue 49: a β-strand

Full ACVR2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACVR2A c.1347+1G>A Uncertain significance ★ same type
ACVR2A p.Ala157Val Uncertain significance ★ ⚠ same type
ACVR2A p.Ala4Val Uncertain significance ★ ⚠ same type
ACVR2A p.Arg162Gly Uncertain significance ★ ⚠ same type
ACVR2A p.Arg24Gly Uncertain significance ★ same type
ACVR2A p.Arg363Gln Uncertain significance ★ ⚠ same type
ACVR2A p.Asn108Ser Uncertain significance ★ ⚠ same type
ACVR2A p.Asn332Thr 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/acvr2a-p-pro49leu (accessed [today's date]).

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