Is ROCK2 p.Glu751Asp (c.2253G>C) pathogenic?

ROCK2 p.Glu751Asp (c.2253G>C) is classified Uncertain significance in ROCK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: ambiguous (0.3839); Ultra-rare (popmax 0.0737%, nfe).

How common is ROCK2 p.Glu751Asp (c.2253G>C) in the general population?

ROCK2 p.Glu751Asp (c.2253G>C) is ultra-rare (popmax 0.0737%, nfe) (gnomAD).

What do computational predictors say about ROCK2 p.Glu751Asp (c.2253G>C)?

AlphaMissense predicts ambiguous (score 0.3839) — an in-silico prediction, not a clinical call.

ROCK2 p.Glu751Asp

c.2253G>C · rs201820613 · VCV3155686

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3839 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0737%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3839	ambiguous
REVEL	0.236	benign-leaning
SaProt	LLR -8.36	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP -3.4, phastCons 0.94
Regional constraint	o/e 0.81	unconstrained · MANE · 23 kb · p 5.3e-07 · regional, not allelic
Overall
CADD	16.94	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 0.0737% European (non-Finnish) · 842/1,142,062 alleles

Filtering AF 0.0696% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0679%

Overall 0.0625% 971/1,553,596 alleles · ultra-rare exomes 892/1,401,530 · genomes 79/152,066 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.11%	912
European (non-Finnish)grpmax	0.0737%	1,356
Remaining individualsnot grpmax-eligible	0.0691%	1,446
Admixed American	0.0671%	1,490
Finnishnot grpmax-eligible	0.0459%	2,177
African / African-American	0.0203%	4,933
South Asian	0.0062%	16,140

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ROCK2
Protein: p.Glu751Asp
Coding: c.2253G>C
MANE Select: NM_004850
dbSNP: rs201820613
Type: single nucleotide variant
Location: chr2:11208398 (GRCh38)
Gene constraint: LOEUF 0.346 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.79 · 23 PDB
Residue 751: the 'required for interaction with foxm1 isoform 5 (foxm1d)' region; the 'interaction with ppp1r12a' region

Full ROCK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ROCK2 c.3609-11A>C Benign ★★ same type
ROCK2 p.Thr431Asn Benign ★★ same type
ROCK2 p.Ala1013Thr Uncertain significance ★ ⚠ same type
ROCK2 p.Ala1018Thr Uncertain significance ★ ⚠ same type
ROCK2 p.Ala663Thr Uncertain significance ★ ⚠ same type
ROCK2 p.Ala663Val Uncertain significance ★ ⚠ same type
ROCK2 p.Arg1044Ter Uncertain significance ★ same type
ROCK2 p.Arg1050His 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/rock2-p-glu751asp (accessed [today's date]).

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