Is CC2D1B p.Leu169Ser (c.506T>C) pathogenic?

CC2D1B p.Leu169Ser (c.506T>C) is classified Uncertain significance in CC2D1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-25). AlphaMissense: likely benign (0.2189); Very rare (popmax 0.00445%, eas).

How common is CC2D1B p.Leu169Ser (c.506T>C) in the general population?

CC2D1B p.Leu169Ser (c.506T>C) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about CC2D1B p.Leu169Ser (c.506T>C)?

AlphaMissense predicts likely benign (score 0.2189) — an in-silico prediction, not a clinical call.

CC2D1B p.Leu169Ser

c.506T>C · VCV3485785

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2189 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2189	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -11.97	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.47, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 11 kb · p 0.15 · regional, not allelic
Overall
CADD	22.8	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 0.00445% East Asian · 2/44,894 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000558% 9/1,614,010 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,447
African / African-American	0.004%	24,981
Remaining individualsnot grpmax-eligible	0.0032%	31,244
South Asian	0.0011%	91,080
European (non-Finnish)	8.47e-05%	1,180,043

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.Leu169Ser
Coding: c.506T>C
MANE Select: NM_001330585
Type: single nucleotide variant
Location: chr1:52360521 (GRCh38)
Gene constraint: LOEUF 0.978 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.98

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-leu169ser (accessed [today's date]).

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