Is ACVR2A p.Glu234Lys (c.700G>A) pathogenic?

ACVR2A p.Glu234Lys (c.700G>A) is classified Uncertain significance in ACVR2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: ambiguous (0.4897); Very rare (popmax 0.00223%, eas).

How common is ACVR2A p.Glu234Lys (c.700G>A) in the general population?

ACVR2A p.Glu234Lys (c.700G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ACVR2A p.Glu234Lys (c.700G>A)?

AlphaMissense predicts ambiguous (score 0.4897) — an in-silico prediction, not a clinical call.

ACVR2A p.Glu234Lys

c.700G>A · VCV4637227

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4897 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4897	ambiguous
REVEL	0.867	moderately pathogenic-leaning
SaProt	LLR -11.55	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 27 kb · p 6.6e-34 · 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

Grpmax group 0.00223% East Asian · 1/44,748 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000558% 9/1,611,662 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,748
Remaining individualsnot grpmax-eligible	0.0016%	62,360
African / African-American	0.00134%	74,760
South Asian	0.0011%	90,918
European (non-Finnish)	0.000424%	235,728

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.Glu234Lys
Coding: c.700G>A
MANE Select: NM_001616
Type: single nucleotide variant
Location: chr2:147917310 (GRCh38)
Gene constraint: LOEUF 0.222 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.20 · 5 PDB
Residue 234: an α-helix; the protein kinase domain

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-glu234lys (accessed [today's date]).

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