Is CS p.Arg340Gln (c.1019G>A) pathogenic?

CS p.Arg340Gln (c.1019G>A) is classified Uncertain significance in CS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-17). AlphaMissense: likely benign (0.1207); Ultra-rare (popmax 0.0652%, sas).

How common is CS p.Arg340Gln (c.1019G>A) in the general population?

CS p.Arg340Gln (c.1019G>A) is ultra-rare (popmax 0.0652%, sas) (gnomAD).

What do computational predictors say about CS p.Arg340Gln (c.1019G>A)?

AlphaMissense predicts likely benign (score 0.1207) — an in-silico prediction, not a clinical call.

CS p.Arg340Gln

c.1019G>A · rs575942993 · VCV2210263

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1207 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0652%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1207	likely benign
REVEL	0.201	benign-leaning
SaProt	LLR -7.30	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 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 13 kb · p 7.5e-36 · regional, not allelic
Overall
CADD	22.9	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 0.0652% South Asian · 55/84,364 alleles

Filtering AF 0.0514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0464%

Overall 0.00661% 104/1,572,942 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0652%	1,534
African / African-American	0.00684%	14,625
Remaining individualsnot grpmax-eligible	0.00659%	15,183
East Asian	0.00449%	22,258
European (non-Finnish)	0.00318%	31,399
Admixed American	0.00195%	51,310

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.Arg340Gln
Coding: c.1019G>A
MANE Select: NM_004077
dbSNP: rs575942993
Type: single nucleotide variant
Location: chr12:56274778 (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-arg340gln (accessed [today's date]).

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