Is ROR2 p.Leu421Val (c.1261C>G) pathogenic?

ROR2 p.Leu421Val (c.1261C>G) is classified Benign in ROR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-15). AlphaMissense: likely benign (0.1698); Rare (popmax 0.201%, sas).

How common is ROR2 p.Leu421Val (c.1261C>G) in the general population?

ROR2 p.Leu421Val (c.1261C>G) is rare (popmax 0.201%, sas) (gnomAD).

What do computational predictors say about ROR2 p.Leu421Val (c.1261C>G)?

AlphaMissense predicts likely benign (score 0.1698) — an in-silico prediction, not a clinical call.

ROR2 p.Leu421Val

c.1261C>G · rs543117428 · VCV2962302

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1698 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.201%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1698	likely benign
REVEL	0.388	indeterminate
SaProt	LLR -6.53	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 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	22.5	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 0.201% South Asian · 183/91,052 alleles

Filtering AF 0.177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.168%

Overall 0.0118% 191/1,613,996 alleles · rare exomes 185/1,461,882 · genomes 6/152,114 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.201%	498
Middle Eastern	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.0096%	10,418
African / African-American	0.00133%	74,986

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: ROR2
Protein: p.Leu421Val
Coding: c.1261C>G
MANE Select: NM_004560
dbSNP: rs543117428
Type: single nucleotide variant
Location: chr9:91726666 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB

Full ROR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ROR2 c.175+1G>A Likely pathogenic ★★ same type
ROR2 p.Arg119Ter Pathogenic ★★ same type
ROR2 p.Arg397Ter Pathogenic ★★ same type
ROR2 p.Arg442Ter Pathogenic ★★ same type
ROR2 p.Arg528Ter Pathogenic/Likely pathogenic ★★ same type
ROR2 c.175+3G>T Uncertain significance ★★ same type
ROR2 c.-102G>T Uncertain significance ★★ same type
ROR2 c.*135G>T 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/ror2-p-leu421val (accessed [today's date]).

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