Is LCP2 p.Pro408Ser (c.1222C>T) pathogenic?

LCP2 p.Pro408Ser (c.1222C>T) is classified Uncertain significance in LCP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). AlphaMissense: likely benign (0.067); Very rare (popmax 0.000764%, nfe).

How common is LCP2 p.Pro408Ser (c.1222C>T) in the general population?

LCP2 p.Pro408Ser (c.1222C>T) is very rare (popmax 0.000764%, nfe) (gnomAD).

What do computational predictors say about LCP2 p.Pro408Ser (c.1222C>T)?

AlphaMissense predicts likely benign (score 0.067) — an in-silico prediction, not a clinical call.

LCP2 p.Pro408Ser

c.1222C>T · VCV4097022

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.067 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000764%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.067	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -5.81	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 -0.038, phastCons 0.99
Regional constraint	o/e 0.95	unconstrained · MANE · 49 kb · p 0.22 · regional, not allelic
Overall
CADD	11.2	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 0.000764% European (non-Finnish) · 9/1,178,506 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000559% 9/1,611,138 alleles · very rare exomes 8/1,458,994 · genomes 1/152,144 · joint denominator

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.Pro408Ser
Coding: c.1222C>T
MANE Select: NM_005565
Type: single nucleotide variant
Location: chr5:170253142 (GRCh38)
Gene constraint: LOEUF 0.465 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.50 · 5 PDB
Residue 408: the 'disordered' region

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

Similar variants

LCP2 p.Pro408Thr Uncertain significance ★ ⚠ same residue
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

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-pro408ser (accessed [today's date]).

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