Is ACVR1 p.Met34fs (c.100_101del) pathogenic?

ACVR1 p.Met34fs (c.100101del) is classified Uncertain significance in ACVR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). Very rare (popmax 0.00195%, nfe).

How common is ACVR1 p.Met34fs (c.100_101del) in the general population?

ACVR1 p.Met34fs (c.100_101del) is very rare (popmax 0.00195%, nfe) (gnomAD).

ACVR1 p.Met34fs

c.100_101del · rs752191696 · VCV3019117

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00195% European (non-Finnish) · 23/1,179,918 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00155% 25/1,612,994 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,301
Admixed American	0.00167%	59,886
African / African-American	0.00134%	74,454

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: ACVR1
Protein: p.Met34fs
Coding: c.100_101del
MANE Select: NM_001111067
dbSNP: rs752191696
Type: Deletion
Location: chr2:157780567 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.70 · 85 PDB
Residue 34: a β-strand

Full ACVR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACVR1 c.332-12_361del Uncertain significance ★ same type
ACVR1 p.His286fs Uncertain significance ★ same type
ACVR1 p.Ile262_Leu263insTer Uncertain significance ★ same type
ACVR1 p.Leu495fs Uncertain significance ★ same type
ACVR1 p.Pro482fs Uncertain significance ★ same type
ACVR1 c.1395+20del Likely benign ★ same type
ACVR1 c.644-19del Likely benign ★ same type
ACVR1 c.67+10_67+11del Likely benign ★ 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/acvr1-p-met34fs (accessed [today's date]).

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