Is CCDC174 p.Arg366His (c.1097G>A) pathogenic?

CCDC174 p.Arg366His (c.1097G>A) is classified Uncertain significance in CCDC174 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). AlphaMissense: likely benign (0.1307); Ultra-rare (popmax 0.0165%, mid).

How common is CCDC174 p.Arg366His (c.1097G>A) in the general population?

CCDC174 p.Arg366His (c.1097G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CCDC174 p.Arg366His (c.1097G>A)?

AlphaMissense predicts likely benign (score 0.1307) — an in-silico prediction, not a clinical call.

CCDC174 p.Arg366His

c.1097G>A · rs370988051 · VCV2226378

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1307 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1307	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -9.77	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 9.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 19 kb · p 0.15 · regional, not allelic
Overall
CADD	32.0	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 0.0165% Middle Eastern · 1/6,064 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00354% 57/1,608,802 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,064
Remaining individualsnot grpmax-eligible	0.00482%	20,748
European (non-Finnish)	0.00399%	25,076
African / African-American	0.00269%	37,232
East Asian	0.00224%	44,738
South Asian	0.00222%	45,018
Admixed American	0.00171%	58,350

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: CCDC174
Protein: p.Arg366His
Coding: c.1097G>A
MANE Select: NM_016474
dbSNP: rs370988051
Type: single nucleotide variant
Location: chr3:14670078 (GRCh38)
Gene constraint: LOEUF 0.926 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.79

Full CCDC174 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC174 p.Arg366Cys Uncertain significance ★ ⚠ same residue
CCDC174 p.Arg366= Likely benign ★ same residue
CCDC174 p.Asp395His Uncertain significance ★★ ⚠ same type
CCDC174 p.Phe29Ser Uncertain significance ★★ ⚠ same type
CCDC174 p.Pro158Ser Uncertain significance ★★ ⚠ same type
CCDC174 c.1106-10T>A Benign/Likely benign ★★ same type
CCDC174 c.308-55C>A Benign ★★ same type
CCDC174 c.485+47G>A Benign ★★ 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/ccdc174-p-arg366his (accessed [today's date]).

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