Is CCS p.Val53Glu (c.158T>A) pathogenic?

CCS p.Val53Glu (c.158T>A) is classified Uncertain significance in CCS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely pathogenic (0.9564); Absent from gnomAD v4.1.

How common is CCS p.Val53Glu (c.158T>A) in the general population?

CCS p.Val53Glu (c.158T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCS p.Val53Glu (c.158T>A)?

AlphaMissense predicts likely pathogenic (score 0.9564) — an in-silico prediction, not a clinical call.

CCS p.Val53Glu

c.158T>A · VCV3997815

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9564 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9564	likely pathogenic · top 4% in CCS
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -16.15	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.085 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CCS
Protein: p.Val53Glu
Coding: c.158T>A
MANE Select: NM_005125
Type: single nucleotide variant
Location: chr11:66599161 (GRCh38)
Gene constraint: LOEUF 1.193 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.54 · 7 PDB
Residue 53: the hma domain; 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-val53glu (accessed [today's date]).

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