Is CCS p.Arg224Ser (c.672G>T) pathogenic?

CCS p.Arg224Ser (c.672G>T) is classified Uncertain significance in CCS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). AlphaMissense: ambiguous (0.513); Ultra-rare (popmax 0.0339%, mid).

How common is CCS p.Arg224Ser (c.672G>T) in the general population?

CCS p.Arg224Ser (c.672G>T) is ultra-rare (popmax 0.0339%, mid) (gnomAD).

What do computational predictors say about CCS p.Arg224Ser (c.672G>T)?

AlphaMissense predicts ambiguous (score 0.513) — an in-silico prediction, not a clinical call.

CCS p.Arg224Ser

c.672G>T · VCV4222315

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.513 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0339%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.513	ambiguous
REVEL	0.887	moderately pathogenic-leaning
SaProt	LLR -12.15	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.37	acceptor gain · deltas
Pangolin	Δ0.20	loss · gain 0.11 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 5.1	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.085 · regional, not allelic
Overall
CADD	31.0	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 0.0339% Middle Eastern · 2/5,896 alleles

Filtering AF 0.00597% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00248%

Overall 0.000823% 13/1,579,958 alleles · ultra-rare exomes 10/1,427,634 · genomes 3/152,324 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0339%	2,948
East Asian	0.00224%	44,558
European (non-Finnish)	0.00086%	116,242

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.Arg224Ser
Coding: c.672G>T
MANE Select: NM_005125
Type: single nucleotide variant
Location: chr11:66605702 (GRCh38)
Gene constraint: LOEUF 1.193 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.54 · 7 PDB
Residue 224: 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-arg224ser (accessed [today's date]).

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