Is CCS p.Ala268= (c.804G>A) pathogenic?

CCS p.Ala268= (c.804G>A) is classified Benign in CCS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-11-12). Common (popmax 16.9%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with CCS-related disorder.

What condition is associated with CCS p.Ala268= (c.804G>A)?

CCS p.Ala268= (c.804G>A) is associated with CCS-related disorder (ClinVar).

CCS p.Ala268=

Q: How common is CCS p.Ala268= (c.804G>A) in the general population?

CCS p.Ala268= (c.804G>A) is common (popmax 16.9%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.804G>A · rs1127145 · VCV3057199

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 16.9%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

CCS-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.65	GERP -2.9
Overall
CADD	5.341	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 16.9% European (non-Finnish) · 195,214/1,155,288 alleles

Filtering AF 16.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 16.8%

Overall 15.2% 237,845/1,563,720 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	19.5%	5
European (non-Finnish)grpmax	16.9%	6
Finnishnot grpmax-eligible	16.8%	6
South Asian	15.3%	7
Remaining individualsnot grpmax-eligible	13.9%	7
Ashkenazi Jewishnot grpmax-eligible	12.2%	8
Middle Eastern	10.8%	9
Admixed American	7.55%	13
African / African-American	2.81%	36
East Asian	2.42%	41

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala268=
Coding: c.804G>A
MANE Select: NM_005125
dbSNP: rs1127145
Type: single nucleotide variant
Location: chr11:66605834 (GRCh38)
Gene constraint: LOEUF 1.193 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.54 · 7 PDB

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

Disease context

CCS-related disorder

Similar variants

CCS p.Leu93= Likely benign same condition
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

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-ala268 (accessed [today's date]).

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