Is CCDC59 p.Ser83Phe (c.248C>T) pathogenic?

CCDC59 p.Ser83Phe (c.248C>T) is classified Uncertain significance in CCDC59 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-27). AlphaMissense: likely benign (0.2422); Very rare (popmax 0.00373%, nfe).

How common is CCDC59 p.Ser83Phe (c.248C>T) in the general population?

CCDC59 p.Ser83Phe (c.248C>T) is very rare (popmax 0.00373%, nfe) (gnomAD).

What do computational predictors say about CCDC59 p.Ser83Phe (c.248C>T)?

AlphaMissense predicts likely benign (score 0.2422) — an in-silico prediction, not a clinical call.

CCDC59 p.Ser83Phe

c.248C>T · VCV3486775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2422 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2422	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 8.4	GERP 1.8, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 5,222 bp · p 4.2e-06 · regional, not allelic
Overall
CADD	26.9	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 0.00373% European (non-Finnish) · 44/1,179,906 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00291% 47/1,613,904 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00373%	26,816
African / African-American	0.00267%	37,460
Finnishnot grpmax-eligible	0.00156%	64,024

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: CCDC59
Protein: p.Ser83Phe
Coding: c.248C>T
MANE Select: NM_014167
Type: single nucleotide variant
Location: chr12:82357176 (GRCh38)
Gene constraint: LOEUF 1.185 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.09

Full CCDC59 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC59 p.Ala184Val Uncertain significance ★ ⚠ same type
CCDC59 p.Arg109Gly Uncertain significance ★ ⚠ same type
CCDC59 p.Arg11Trp Uncertain significance ★ ⚠ same type
CCDC59 p.Arg50Cys Uncertain significance ★ ⚠ same type
CCDC59 p.Arg5Gly Uncertain significance ★ ⚠ same type
CCDC59 p.Arg6Gly Uncertain significance ★ ⚠ same type
CCDC59 p.Asn216Lys Uncertain significance ★ ⚠ same type
CCDC59 p.Asp131Glu 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/ccdc59-p-ser83phe (accessed [today's date]).

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