Is CC2D1B p.Arg305His (c.914G>A) pathogenic?

CC2D1B p.Arg305His (c.914G>A) is classified Uncertain significance in CC2D1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28). AlphaMissense: likely benign (0.0743); Ultra-rare (popmax 0.0202%, eas).

How common is CC2D1B p.Arg305His (c.914G>A) in the general population?

CC2D1B p.Arg305His (c.914G>A) is ultra-rare (popmax 0.0202%, eas) (gnomAD).

What do computational predictors say about CC2D1B p.Arg305His (c.914G>A)?

AlphaMissense predicts likely benign (score 0.0743) — an in-silico prediction, not a clinical call.

CC2D1B p.Arg305His

c.914G>A · VCV3996233

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0743 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0202%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0743	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -11.52	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 -0.77	GERP -2.2
Regional constraint	o/e 1.04	unconstrained · MANE · 11 kb · p 0.15 · regional, not allelic
Overall
CADD	16.98	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 0.0202% East Asian · 9/44,538 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00784%

Overall 0.00218% 35/1,607,646 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0202%	4,949
African / African-American	0.00401%	24,909
European (non-Finnish)	0.0017%	58,859
Admixed American	0.00169%	59,204
Remaining individualsnot grpmax-eligible	0.00161%	62,228
South Asian	0.00111%	89,816

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.Arg305His
Coding: c.914G>A
MANE Select: NM_001330585
Type: single nucleotide variant
Location: chr1:52359733 (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.Arg305Cys Uncertain significance ★ ⚠ same residue
CC2D1B p.Arg305Leu Uncertain significance ★ ⚠ same residue
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

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-arg305his (accessed [today's date]).

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