Is CCS p.Arg178Cys (c.532C>T) pathogenic?

CCS p.Arg178Cys (c.532C>T) is classified Likely benign in CCS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.247); Very rare (popmax 0.004%, afr).

How common is CCS p.Arg178Cys (c.532C>T) in the general population?

CCS p.Arg178Cys (c.532C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about CCS p.Arg178Cys (c.532C>T)?

AlphaMissense predicts likely benign (score 0.247) — an in-silico prediction, not a clinical call.

CCS p.Arg178Cys

c.532C>T · VCV4222312

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.247 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.247	likely benign
REVEL	0.566	indeterminate
SaProt	LLR -8.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.33, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.085 · regional, not allelic
Overall
CADD	23.7	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 0.004% African / African-American · 3/74,912 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00192% 31/1,614,028 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,971
Admixed American	0.00333%	29,999
European (non-Finnish)	0.00203%	49,168
Finnishnot grpmax-eligible	0.00156%	64,030
South Asian	0.0011%	91,084

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.Arg178Cys
Coding: c.532C>T
MANE Select: NM_005125
Type: single nucleotide variant
Location: chr11:66605381 (GRCh38)
Gene constraint: LOEUF 1.193 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.54 · 7 PDB
Residue 178: a disulfide bond; the 'superoxide dismutase-like' region

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-arg178cys (accessed [today's date]).

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