Is CCDC175 p.Arg354Pro (c.1061G>C) pathogenic?

CCDC175 p.Arg354Pro (c.1061G>C) is classified Uncertain significance in CCDC175 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely pathogenic (0.6269); Ultra-rare (popmax 0.0196%, amr).

How common is CCDC175 p.Arg354Pro (c.1061G>C) in the general population?

CCDC175 p.Arg354Pro (c.1061G>C) is ultra-rare (popmax 0.0196%, amr) (gnomAD).

What do computational predictors say about CCDC175 p.Arg354Pro (c.1061G>C)?

AlphaMissense predicts likely pathogenic (score 0.6269) — an in-silico prediction, not a clinical call.

CCDC175 p.Arg354Pro

c.1061G>C · rs765447358 · VCV2339936

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6269 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0196%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6269	likely pathogenic · top 5% in CCDC175
REVEL	0.032	moderately benign-leaning
SaProt	LLR -12.85	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.2	GERP -2.3
Regional constraint	o/e 0.96	unconstrained · MANE · 72 kb · p 0.21 · regional, not allelic
Overall
CADD	12.83	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 0.0196% Admixed American · 10/50,944 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0081%

Overall 0.000716% 11/1,536,498 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0196%	5,094
European (non-Finnish)	8.72e-05%	1,146,638

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: CCDC175
Protein: p.Arg354Pro
Coding: c.1061G>C
MANE Select: NM_001164399
dbSNP: rs765447358
Type: single nucleotide variant
Location: chr14:59545274 (GRCh38)
Gene constraint: LOEUF 1.235 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.01

Full CCDC175 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC175 p.Arg354His Uncertain significance ★ ⚠ same residue
CCDC175 p.Ala124Thr Uncertain significance ★ ⚠ same type
CCDC175 p.Ala219Val Uncertain significance ★ ⚠ same type
CCDC175 p.Ala228Pro Uncertain significance ★ ⚠ same type
CCDC175 p.Ala316Val Uncertain significance ★ ⚠ same type
CCDC175 p.Ala353Pro Uncertain significance ★ ⚠ same type
CCDC175 p.Ala429Ser Uncertain significance ★ ⚠ same type
CCDC175 p.Arg122Gln 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/ccdc175-p-arg354pro (accessed [today's date]).

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