Is ROCK2 p.Phe136Cys (c.407T>G) pathogenic?

ROCK2 p.Phe136Cys (c.407T>G) is classified Likely benign in ROCK2 (ClinVar, Single submitter, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely pathogenic (0.9536); Ultra-rare (popmax 0.0745%, nfe).

How common is ROCK2 p.Phe136Cys (c.407T>G) in the general population?

ROCK2 p.Phe136Cys (c.407T>G) is ultra-rare (popmax 0.0745%, nfe) (gnomAD).

What do computational predictors say about ROCK2 p.Phe136Cys (c.407T>G)?

AlphaMissense predicts likely pathogenic (score 0.9536) — an in-silico prediction, not a clinical call.

ROCK2 p.Phe136Cys

c.407T>G · rs201939803 · VCV755774

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9536 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0745%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9536	likely pathogenic
REVEL	0.596	indeterminate
SaProt	LLR -7.05	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 123 kb · p 2.4e-21 · regional, not allelic
Overall
CADD	27.5	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 0.0745% European (non-Finnish) · 870/1,167,844 alleles

Filtering AF 0.0704% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0687%

Overall 0.0703% 1,114/1,585,758 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.318%	314
Amishnot grpmax-eligible	0.219%	456
European (non-Finnish)grpmax	0.0745%	1,342
Remaining individualsnot grpmax-eligible	0.0555%	1,803
African / African-American	0.00538%	18,575
Admixed American	0.00355%	28,130

Finnish 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.Phe136Cys
Coding: c.407T>G
MANE Select: NM_004850
dbSNP: rs201939803
Type: single nucleotide variant
Location: chr2:11249716 (GRCh38)
Gene constraint: LOEUF 0.346 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.79 · 23 PDB
Residue 136: the protein kinase domain

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-phe136cys (accessed [today's date]).

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