Is LMOD2 p.Arg231Cys (c.691C>T) pathogenic?

LMOD2 p.Arg231Cys (c.691C>T) is classified Uncertain significance in LMOD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-11). AlphaMissense: likely benign (0.109); Ultra-rare (popmax 0.0484%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LMOD2 p.Arg231Cys (c.691C>T)?

LMOD2 p.Arg231Cys (c.691C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LMOD2 p.Arg231Cys (c.691C>T) in the general population?

LMOD2 p.Arg231Cys (c.691C>T) is ultra-rare (popmax 0.0484%, nfe) (gnomAD).

What do computational predictors say about LMOD2 p.Arg231Cys (c.691C>T)?

AlphaMissense predicts likely benign (score 0.109) — an in-silico prediction, not a clinical call.

LMOD2 p.Arg231Cys

c.691C>T · rs368348168 · VCV2455225

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.109 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0484%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.109	likely benign
REVEL	0.537	indeterminate
SaProt	LLR -7.57	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 2.7	GERP 0.2, phastCons 0.99
Regional constraint	o/e 0.93	unconstrained · MANE · 7,778 bp · p 0.09 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0484% European (non-Finnish) · 571/1,179,900 alleles

Filtering AF 0.0451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0437%

Overall 0.0389% 628/1,613,876 alleles · ultra-rare exomes 601/1,461,700 · genomes 27/152,176 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0515%	1,940
European (non-Finnish)grpmax	0.0484%	2,066
Remaining individualsnot grpmax-eligible	0.0256%	3,904
East Asian	0.00891%	11,222
African / African-American	0.00267%	37,456
Admixed American	0.00167%	60,006
South Asian	0.0011%	91,082

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: LMOD2
Protein: p.Arg231Cys
Coding: c.691C>T
MANE Select: NM_207163
dbSNP: rs368348168
Type: single nucleotide variant
Location: chr7:123662277 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.14 · 6 PDB
Residue 231: an α-helix; the 'interaction with actin 2' region

Full LMOD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LMOD2 p.Glu276Lys Uncertain significance ★★ ⚠ same condition
LMOD2 p.Thr244Met Uncertain significance ★★ ⚠ same condition
LMOD2 p.Ala23Ser Uncertain significance ★ same condition
LMOD2 p.Ala23Val Uncertain significance ★ ⚠ same condition
LMOD2 p.Ala287Pro Uncertain significance ★ ⚠ same condition
LMOD2 p.Ala287Thr Uncertain significance ★ ⚠ same condition
LMOD2 p.Ala528Val Uncertain significance ★ ⚠ same condition
LMOD2 p.Ala68Glu Uncertain significance ★ ⚠ same condition

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/lmod2-p-arg231cys (accessed [today's date]).

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