Is CC2D1B p.Phe719Leu (c.2157T>A) pathogenic?

CC2D1B p.Phe719Leu (c.2157T>A) is classified Uncertain significance in CC2D1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-29). AlphaMissense: likely pathogenic (0.9861); Very rare (popmax 0.000169%, nfe).

How common is CC2D1B p.Phe719Leu (c.2157T>A) in the general population?

CC2D1B p.Phe719Leu (c.2157T>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CC2D1B p.Phe719Leu (c.2157T>A)?

AlphaMissense predicts likely pathogenic (score 0.9861) — an in-silico prediction, not a clinical call.

CC2D1B p.Phe719Leu

c.2157T>A · VCV3485794

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9861 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9861	likely pathogenic · top 1% in CC2D1B
REVEL	0.596	indeterminate
SaProt	LLR -8.42	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4	GERP -1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 11 kb · p 0.15 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F725L vs ClinVar F719L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,046 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,096 alleles · very 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: CC2D1B
Protein: p.Phe719Leu
Coding: c.2157T>A
MANE Select: NM_001330585
Type: single nucleotide variant
Location: chr1:52355638 (GRCh38)
Gene constraint: LOEUF 0.978 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.98
Residue 719: the c2 domain

Full CC2D1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CC2D1B p.Gly790= Benign ★★ same type
CC2D1B p.His674Tyr Likely benign ★★ same type
CC2D1B p.Leu511= Benign ★★ same type
CC2D1B p.Ala103Gly Uncertain significance ★ ⚠ same type
CC2D1B p.Ala180Ser Uncertain significance ★ ⚠ same type
CC2D1B p.Ala181Thr Uncertain significance ★ ⚠ same type
CC2D1B p.Ala181Val Uncertain significance ★ ⚠ same type
CC2D1B p.Ala208Thr 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/cc2d1b-p-phe719leu (accessed [today's date]).

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