Is CCS p.Gly228Ala (c.683G>C) pathogenic?

CCS p.Gly228Ala (c.683G>C) is classified Uncertain significance in CCS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-28). AlphaMissense: ambiguous (0.3682); Ultra-rare (popmax 0.0686%, sas).

How common is CCS p.Gly228Ala (c.683G>C) in the general population?

CCS p.Gly228Ala (c.683G>C) is ultra-rare (popmax 0.0686%, sas) (gnomAD).

What do computational predictors say about CCS p.Gly228Ala (c.683G>C)?

AlphaMissense predicts ambiguous (score 0.3682) — an in-silico prediction, not a clinical call.

CCS p.Gly228Ala

c.683G>C · rs138370847 · VCV2556322

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3682 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0686%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3682	ambiguous
REVEL	0.693	pathogenic-leaning
SaProt	LLR -8.57	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.085 · regional, not allelic
Overall
CADD	26.9	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 0.0686% South Asian · 60/87,448 alleles

Filtering AF 0.0547% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0496%

Overall 0.0102% 162/1,583,668 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0686%	1,457
European (non-Finnish)	0.00867%	11,530
Remaining individualsnot grpmax-eligible	0.00164%	61,022

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: CCS
Protein: p.Gly228Ala
Coding: c.683G>C
MANE Select: NM_005125
dbSNP: rs138370847
Type: single nucleotide variant
Location: chr11:66605713 (GRCh38)
Gene constraint: LOEUF 1.193 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.54 · 7 PDB
Residue 228: the 'superoxide dismutase-like' region; a β-strand

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

Similar variants

CCS c.567+1G>C Uncertain significance ★ same type
CCS p.Ala173Thr Uncertain significance ★ ⚠ same type
CCS p.Ala179Thr Uncertain significance ★ ⚠ same type
CCS p.Ala234Thr Uncertain significance ★ same type
CCS p.Ala260Ser Uncertain significance ★ ⚠ same type
CCS p.Ala260Thr Uncertain significance ★ ⚠ same type
CCS p.Arg163Gln Uncertain significance ★ ⚠ same type
CCS p.Arg163Gly 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/ccs-p-gly228ala (accessed [today's date]).

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