Is CCDC28B p.Ser46Phe (c.137C>T) pathogenic?

CCDC28B p.Ser46Phe (c.137C>T) is classified Uncertain significance in CCDC28B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: ambiguous (0.4257); Ultra-rare (popmax 0.011%, sas).

How common is CCDC28B p.Ser46Phe (c.137C>T) in the general population?

CCDC28B p.Ser46Phe (c.137C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about CCDC28B p.Ser46Phe (c.137C>T)?

AlphaMissense predicts ambiguous (score 0.4257) — an in-silico prediction, not a clinical call.

CCDC28B p.Ser46Phe

c.137C>T · VCV3996924

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4257 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Computational evidence

Protein change
AlphaMissense	0.4257	ambiguous
REVEL	0.294	indeterminate
SaProt	LLR -7.96	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 3,309 bp · p 0.015 · regional, not allelic
Overall
CADD	28.3	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 0.011% South Asian · 10/90,988 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00454%

Overall 0.000682% 11/1,613,118 alleles · ultra-rare exomes 11/1,460,830 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,099
European (non-Finnish)	8.48e-05%	1,179,544

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: CCDC28B
Protein: p.Ser46Phe
Coding: c.137C>T
MANE Select: NM_024296
Type: single nucleotide variant
Location: chr1:32202072 (GRCh38)
Gene constraint: LOEUF 1.357 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.15
Residue 46: the 'disordered' region; a modified residue (phosphoserine)

Full CCDC28B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC28B p.Lys112= Uncertain significance ★★ same type
CCDC28B p.Arg25Trp Benign ★★ same type
CCDC28B p.Glu154= Benign/Likely benign ★★ same type
CCDC28B p.Gly155Arg Benign/Likely benign ★★ same type
CCDC28B p.Ala199Asp Uncertain significance ★ ⚠ same type
CCDC28B p.Ala20Val Uncertain significance ★ ⚠ same type
CCDC28B p.Ala73Pro Uncertain significance ★ ⚠ same type
CCDC28B p.Ala73Val 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/ccdc28b-p-ser46phe (accessed [today's date]).

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