Is CS p.Leu115Val (c.343C>G) pathogenic?

CS p.Leu115Val (c.343C>G) is classified Uncertain significance in CS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.2777); Very rare (popmax 0.00445%, eas).

How common is CS p.Leu115Val (c.343C>G) in the general population?

CS p.Leu115Val (c.343C>G) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about CS p.Leu115Val (c.343C>G)?

AlphaMissense predicts likely benign (score 0.2777) — an in-silico prediction, not a clinical call.

CS p.Leu115Val

c.343C>G · VCV4007274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2777 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2777	likely benign
REVEL	0.434	indeterminate
SaProt	LLR -11.41	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -1.4, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 13 kb · p 7.5e-36 · regional, not allelic
Overall
CADD	21.8	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 0.00445% East Asian · 2/44,900 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,614,078 alleles · very rare

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: CS
Protein: p.Leu115Val
Coding: c.343C>G
MANE Select: NM_004077
Type: single nucleotide variant
Location: chr12:56282916 (GRCh38)
Gene constraint: LOEUF 0.356 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.56 · 11 PDB

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

Similar variants

CS p.Leu257= Benign ★★ same type
CS p.Phe96= Benign ★★ same type
CS p.Ala2Gly Uncertain significance ★ ⚠ same type
CS p.Ala8Ser Uncertain significance ★ ⚠ same type
CS p.Arg183Gly Uncertain significance ★ ⚠ same type
CS p.Arg191Gln Uncertain significance ★ ⚠ same type
CS p.Arg218Gln Uncertain significance ★ ⚠ same type
CS p.Arg329Gln 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/cs-p-leu115val (accessed [today's date]).

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