Is CCDC148 p.Arg489Trp (c.1465C>T) pathogenic?

CCDC148 p.Arg489Trp (c.1465C>T) is classified Uncertain significance in CCDC148 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). AlphaMissense: likely benign (0.1754); Ultra-rare (popmax 0.0133%, amr).

How common is CCDC148 p.Arg489Trp (c.1465C>T) in the general population?

CCDC148 p.Arg489Trp (c.1465C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about CCDC148 p.Arg489Trp (c.1465C>T)?

AlphaMissense predicts likely benign (score 0.1754) — an in-silico prediction, not a clinical call.

CCDC148 p.Arg489Trp

c.1465C>T · VCV3828232

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1754 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1754	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -10.20	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -0.14, phastCons 0.93
Regional constraint	o/e 1.03	unconstrained · MANE · 284 kb · p 0.43 · regional, not allelic
Overall
CADD	24.7	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 0.0133% Admixed American · 8/59,930 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00353% 57/1,612,984 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,491
African / African-American	0.00535%	18,706
Remaining individualsnot grpmax-eligible	0.00481%	20,809
South Asian	0.0044%	22,753
European (non-Finnish)	0.00314%	31,877
East Asian	0.00223%	44,820

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: CCDC148
Protein: p.Arg489Trp
Coding: c.1465C>T
MANE Select: NM_138803
Type: single nucleotide variant
Location: chr2:158178902 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.14

Full CCDC148 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC148 p.Gln75Pro Benign ★★ ⚠ same type
CCDC148 p.Glu387= Benign ★★ same type
CCDC148 p.Glu522Lys Benign ★★ same type
CCDC148 p.Tyr307Phe Benign ★★ same type
CCDC148 p.Ala135Thr Uncertain significance ★ ⚠ same type
CCDC148 p.Ala42Pro Uncertain significance ★ ⚠ same type
CCDC148 p.Ala448Ser Uncertain significance ★ ⚠ same type
CCDC148 p.Ala448Thr 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/ccdc148-p-arg489trp (accessed [today's date]).

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