Is CCDC148 p.Ala42Pro (c.124G>C) pathogenic?

CCDC148 p.Ala42Pro (c.124G>C) is classified Uncertain significance in CCDC148 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: ambiguous (0.4773); Rare (popmax 0.41%, afr).

How common is CCDC148 p.Ala42Pro (c.124G>C) in the general population?

CCDC148 p.Ala42Pro (c.124G>C) is rare (popmax 0.41%, afr) (gnomAD).

What do computational predictors say about CCDC148 p.Ala42Pro (c.124G>C)?

AlphaMissense predicts ambiguous (score 0.4773) — an in-silico prediction, not a clinical call.

CCDC148 p.Ala42Pro

c.124G>C · VCV4220618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4773 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.41%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4773	ambiguous
REVEL	0.142	moderately benign-leaning
SaProt	LLR -12.78	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 2.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 284 kb · p 0.43 · regional, not allelic
Overall
CADD	23.8	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 0.41% African / African-American · 306/74,632 alleles

Filtering AF 0.372% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.357%

Overall 0.0203% 327/1,606,886 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.41%	244
Remaining individualsnot grpmax-eligible	0.0193%	5,185
Admixed American	0.0137%	7,325
European (non-Finnish)	8.49e-05%	1,177,740

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.Ala42Pro
Coding: c.124G>C
MANE Select: NM_138803
Type: single nucleotide variant
Location: chr2:158358472 (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.Ala448Ser Uncertain significance ★ ⚠ same type
CCDC148 p.Ala448Thr Uncertain significance ★ ⚠ same type
CCDC148 p.Ala46Val 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-ala42pro (accessed [today's date]).

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