Is LCP2 p.Arg90Trp (c.268C>T) pathogenic?

LCP2 p.Arg90Trp (c.268C>T) is classified Uncertain significance in LCP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-27). AlphaMissense: likely benign (0.197); Ultra-rare (popmax 0.0164%, mid).

How common is LCP2 p.Arg90Trp (c.268C>T) in the general population?

LCP2 p.Arg90Trp (c.268C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about LCP2 p.Arg90Trp (c.268C>T)?

AlphaMissense predicts likely benign (score 0.197) — an in-silico prediction, not a clinical call.

LCP2 p.Arg90Trp

c.268C>T · VCV3537616

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.197 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.197	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -9.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -0.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 49 kb · p 0.22 · regional, not allelic
Overall
CADD	24.6	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.0031% 50/1,613,864 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
European (non-Finnish)	0.00373%	26,815
Remaining individualsnot grpmax-eligible	0.0032%	31,230
African / African-American	0.00267%	37,463
Admixed American	0.00167%	60,008

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: LCP2
Protein: p.Arg90Trp
Coding: c.268C>T
MANE Select: NM_005565
Type: single nucleotide variant
Location: chr5:170275338 (GRCh38)
Gene constraint: LOEUF 0.465 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.50 · 5 PDB
Residue 90: the 'disordered' region

Full LCP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LCP2 p.Arg407Trp Uncertain significance ★★ ⚠ same type
LCP2 p.Pro328Leu Uncertain significance ★★ ⚠ same type
LCP2 c.142-18T>C Benign ★★ same type
LCP2 c.523+16C>T Benign ★★ same type
LCP2 p.Gln326= Benign ★★ same type
LCP2 p.Pro242= Benign ★★ same type
LCP2 p.Ser410Cys Benign/Likely benign ★★ same type
LCP2 p.Val188= Benign ★★ 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/lcp2-p-arg90trp (accessed [today's date]).

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