Is CC2D2A p.Ser1354Phe (c.4061C>T) pathogenic?

CC2D2A p.Ser1354Phe (c.4061C>T) is classified Uncertain significance in CC2D2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-29). AlphaMissense: likely pathogenic (0.9569); Very rare (popmax 8.59e-05%, nfe); Associated with Meckel syndrome, type 6.

What condition is associated with CC2D2A p.Ser1354Phe (c.4061C>T)?

CC2D2A p.Ser1354Phe (c.4061C>T) is associated with Meckel syndrome, type 6, Joubert syndrome 9, retinitis pigmentosa 93 (ClinVar).

How common is CC2D2A p.Ser1354Phe (c.4061C>T) in the general population?

CC2D2A p.Ser1354Phe (c.4061C>T) is very rare (popmax 8.59e-05%, nfe) (gnomAD).

What do computational predictors say about CC2D2A p.Ser1354Phe (c.4061C>T)?

AlphaMissense predicts likely pathogenic (score 0.9569) — an in-silico prediction, not a clinical call.

CC2D2A p.Ser1354Phe

c.4061C>T · VCV3590399

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9569 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.59e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Meckel syndrome, type 6

Computational evidence

Protein change
AlphaMissense	0.9569	likely pathogenic · top 4% in CC2D2A
REVEL	0.501	indeterminate
SaProt	LLR -13.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 1,660 bp · p 0.93 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.59e-05% European (non-Finnish) · 1/1,164,164 alleles

Overall 6.3e-05% 1/1,587,796 alleles · very rare exomes 1/1,435,508 · genomes 0/152,288 · joint denominator

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: CC2D2A
Protein: p.Ser1354Phe
Coding: c.4061C>T
MANE Select: NM_001378615
Type: single nucleotide variant
Location: chr4:15586242 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46

Full CC2D2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Meckel syndrome, type 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome 9 retinitis pigmentosa 93 COACH syndrome 2

Similar variants

CC2D2A c.1017+1G>A Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.1149+1G>A Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.1359+1G>A Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.1359+1G>C Likely pathogenic ★★ same condition
CC2D2A c.1466+1G>A Likely pathogenic ★★ same condition
CC2D2A c.2004-17A>G Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.2486+1G>C Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.2625+1G>A Pathogenic/Likely pathogenic ★★ same condition

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/cc2d2a-p-ser1354phe (accessed [today's date]).

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