Is CCDC146 p.Val28Met (c.82G>A) pathogenic?

CCDC146 p.Val28Met (c.82G>A) is classified Uncertain significance in CCDC146 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-23). AlphaMissense: likely benign (0.1374); Ultra-rare (popmax 0.0285%, amr).

How common is CCDC146 p.Val28Met (c.82G>A) in the general population?

CCDC146 p.Val28Met (c.82G>A) is ultra-rare (popmax 0.0285%, amr) (gnomAD).

What do computational predictors say about CCDC146 p.Val28Met (c.82G>A)?

AlphaMissense predicts likely benign (score 0.1374) — an in-silico prediction, not a clinical call.

CCDC146 p.Val28Met

c.82G>A · VCV3828221

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1374 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0285%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1374	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -7.36	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 2.2	phastCons 0.095
Regional constraint	o/e 0.26	constrained · MANE · 151 bp · p 1.9e-08 · regional, not allelic
Overall
CADD	16.62	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0285% Admixed American · 17/59,722 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0148%

Overall 0.00105% 17/1,611,784 alleles · ultra-rare

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: CCDC146
Protein: p.Val28Met
Coding: c.82G>A
MANE Select: NM_020879
Type: single nucleotide variant
Location: chr7:77167750 (GRCh38)
Gene constraint: LOEUF 0.926 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.78

Full CCDC146 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC146 c.450-1G>T Likely pathogenic ★ same type
CCDC146 p.Arg306Ter Likely pathogenic ★ same type
CCDC146 p.Arg362Ter Pathogenic ★ same type
CCDC146 p.Ala282Ser Uncertain significance ★ ⚠ same type
CCDC146 p.Ala394Asp Uncertain significance ★ ⚠ same type
CCDC146 p.Ala479Thr Uncertain significance ★ same type
CCDC146 p.Ala560Asp Uncertain significance ★ ⚠ same type
CCDC146 p.Ala575Val 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/ccdc146-p-val28met (accessed [today's date]).

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