Is CCDC178 p.Lys515Arg (c.1544A>G) pathogenic?

CCDC178 p.Lys515Arg (c.1544A>G) is classified Uncertain significance in CCDC178 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-07). AlphaMissense: likely benign (0.1021); Ultra-rare (popmax 0.0237%, sas).

How common is CCDC178 p.Lys515Arg (c.1544A>G) in the general population?

CCDC178 p.Lys515Arg (c.1544A>G) is ultra-rare (popmax 0.0237%, sas) (gnomAD).

What do computational predictors say about CCDC178 p.Lys515Arg (c.1544A>G)?

AlphaMissense predicts likely benign (score 0.1021) — an in-silico prediction, not a clinical call.

CCDC178 p.Lys515Arg

c.1544A>G · rs371328695 · VCV2354360

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1021 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0237%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1021	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -7.33	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 2.3	GERP 0.67, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 474 kb · p 0.17 · regional, not allelic
Overall
CADD	20.2	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0237% South Asian · 21/88,700 alleles

Filtering AF 0.0158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0133%

Overall 0.00386% 62/1,604,678 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0237%	4,224
Admixed American	0.0187%	5,339
Middle Eastern	0.0167%	6,004
Remaining individualsnot grpmax-eligible	0.00483%	20,709
European (non-Finnish)	0.00213%	47,038
African / African-American	0.00134%	74,568

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: CCDC178
Protein: p.Lys515Arg
Coding: c.1544A>G
MANE Select: NM_001105528
dbSNP: rs371328695
Type: single nucleotide variant
Location: chr18:33245294 (GRCh38)
Gene constraint: LOEUF 1.347 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.69

Full CCDC178 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC178 p.Ala216Thr Uncertain significance ★ ⚠ same type
CCDC178 p.Ala261Gly Uncertain significance ★ ⚠ same type
CCDC178 p.Ala339Asp Uncertain significance ★ ⚠ same type
CCDC178 p.Ala339Thr Uncertain significance ★ ⚠ same type
CCDC178 p.Ala375Thr Uncertain significance ★ ⚠ same type
CCDC178 p.Ala563Thr Uncertain significance ★ ⚠ same type
CCDC178 p.Ala574Glu Uncertain significance ★ ⚠ same type
CCDC178 p.Ala666Thr 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/ccdc178-p-lys515arg (accessed [today's date]).

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