Is CT55 p.Arg99His (c.296G>A) pathogenic?

CT55 p.Arg99His (c.296G>A) is classified Likely benign in CT55 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.058); Ultra-rare (popmax 0.0395%, amr).

How common is CT55 p.Arg99His (c.296G>A) in the general population?

CT55 p.Arg99His (c.296G>A) is ultra-rare (popmax 0.0395%, amr) (gnomAD).

What do computational predictors say about CT55 p.Arg99His (c.296G>A)?

AlphaMissense predicts likely benign (score 0.058) — an in-silico prediction, not a clinical call.

CT55 p.Arg99His

c.296G>A · VCV4235403

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.058 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.058	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -5.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.093	GERP -2.5
Regional constraint	o/e 0.80	unconstrained · MANE · 14 kb · p 0.023 · regional, not allelic
Overall
CADD	0.694	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 0.0395% Admixed American · 16/40,520 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0201%

Overall 0.00219% 26/1,187,717 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0395%	2,532
Remaining individualsnot grpmax-eligible	0.00644%	15,526
European (non-Finnish)	0.000788%	126,943

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: CT55
Protein: p.Arg99His
Coding: c.296G>A
MANE Select: NM_001031705
Type: single nucleotide variant
Location: chrX:135160539 (GRCh38)
Structure: AlphaFold pLDDT 75.60

Full CT55 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CT55 p.Arg99Cys Uncertain significance ★ ⚠ same residue
CT55 p.Ala104Ser Uncertain significance ★ ⚠ same type
CT55 p.Ala166Ser Uncertain significance ★ ⚠ same type
CT55 p.Ala166Thr Uncertain significance ★ ⚠ same type
CT55 p.Asp149Asn Uncertain significance ★ ⚠ same type
CT55 p.Asp83Gly Uncertain significance ★ ⚠ same type
CT55 p.Glu152Lys Uncertain significance ★ ⚠ same type
CT55 p.Glu55Gly 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/ct55-p-arg99his (accessed [today's date]).

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