Is CCDC112 p.Arg391Cys (c.1171C>T) pathogenic?

CCDC112 p.Arg391Cys (c.1171C>T) is classified Uncertain significance in CCDC112 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.0823); Ultra-rare (popmax 0.0335%, afr).

How common is CCDC112 p.Arg391Cys (c.1171C>T) in the general population?

CCDC112 p.Arg391Cys (c.1171C>T) is ultra-rare (popmax 0.0335%, afr) (gnomAD).

What do computational predictors say about CCDC112 p.Arg391Cys (c.1171C>T)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

CCDC112 p.Arg391Cys

c.1171C>T · VCV4220309

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0335%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0823	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -8.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 29 kb · p 0.025 · regional, not allelic
Overall
CADD	25.3	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R308C vs ClinVar R391C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0335% African / African-American · 25/74,730 alleles

Filtering AF 0.0232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00403% 65/1,611,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0335%	2,989
East Asian	0.0156%	6,399
South Asian	0.00445%	22,455
Finnishnot grpmax-eligible	0.00313%	31,906
European (non-Finnish)	0.0022%	45,365
Admixed American	0.00168%	59,552

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: CCDC112
Protein: p.Arg391Cys
Coding: c.1171C>T
MANE Select: NM_001040440
Type: single nucleotide variant
Location: chr5:115271374 (GRCh38)
Gene constraint: LOEUF 0.875 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.18
Residue 391: the 'disordered' region

Full CCDC112 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC112 p.Arg391His Uncertain significance ★ ⚠ same residue
CCDC112 p.Arg391Leu Uncertain significance ★ ⚠ same residue
CCDC112 p.Ala165Val Uncertain significance ★ ⚠ same type
CCDC112 p.Ala299Ser Uncertain significance ★ ⚠ same type
CCDC112 p.Ala434Pro Uncertain significance ★ ⚠ same type
CCDC112 p.Ala68Pro Uncertain significance ★ same type
CCDC112 p.Arg393Leu Uncertain significance ★ ⚠ same type
CCDC112 p.Arg51Cys 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/ccdc112-p-arg391cys (accessed [today's date]).

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