Is CS p.Ala2Gly (c.5C>G) pathogenic?

CS p.Ala2Gly (c.5C>G) is classified Uncertain significance in CS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: likely benign (0.1092); Rare (popmax 0.206%, mid).

How common is CS p.Ala2Gly (c.5C>G) in the general population?

CS p.Ala2Gly (c.5C>G) is rare (popmax 0.206%, mid) (gnomAD).

What do computational predictors say about CS p.Ala2Gly (c.5C>G)?

AlphaMissense predicts likely benign (score 0.1092) — an in-silico prediction, not a clinical call.

CS p.Ala2Gly

c.5C>G · rs147086028 · VCV2350874

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1092 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.206%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1092	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -10.03	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 14 kb · p 0.074 · regional, not allelic
Overall
CADD	24.6	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 0.206% Middle Eastern · 9/4,360 alleles

Filtering AF 0.108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0804%

Overall 0.0115% 181/1,568,544 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.206%	484
Ashkenazi Jewishnot grpmax-eligible	0.132%	757
Admixed American	0.0396%	2,523
Remaining individualsnot grpmax-eligible	0.0264%	3,788
European (non-Finnish)	0.00759%	13,167
Finnishnot grpmax-eligible	0.00492%	20,310
African / African-American	0.00409%	24,468
South Asian	0.00349%	28,627

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.Ala2Gly
Coding: c.5C>G
MANE Select: NM_004077
dbSNP: rs147086028
Type: single nucleotide variant
Location: chr12:56300197 (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.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
CS p.Arg340Gln 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-ala2gly (accessed [today's date]).

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