Is CCDC157 p.Pro622Leu (c.1865C>T) pathogenic?

CCDC157 p.Pro622Leu (c.1865C>T) is classified Uncertain significance in CCDC157 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: likely benign (0.1741); Ultra-rare (popmax 0.0354%, nfe).

How common is CCDC157 p.Pro622Leu (c.1865C>T) in the general population?

CCDC157 p.Pro622Leu (c.1865C>T) is ultra-rare (popmax 0.0354%, nfe) (gnomAD).

What do computational predictors say about CCDC157 p.Pro622Leu (c.1865C>T)?

AlphaMissense predicts likely benign (score 0.1741) — an in-silico prediction, not a clinical call.

CCDC157 p.Pro622Leu

c.1865C>T · rs753475863 · VCV2361317

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1741 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0354%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1741	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -6.00	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 4.7	GERP 0.51, phastCons 0.99
Regional constraint	o/e 0.96	unconstrained · MANE · 11 kb · p 0.19 · regional, not allelic
Overall
CADD	23.0	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 0.0354% European (non-Finnish) · 417/1,176,540 alleles

Filtering AF 0.0326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0315%

Overall 0.0278% 447/1,607,602 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0354%	2,821
Remaining individualsnot grpmax-eligible	0.0306%	3,273
Admixed American	0.0118%	8,481
African / African-American	0.00405%	24,667
East Asian	0.00223%	44,826

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: CCDC157
Protein: p.Pro622Leu
Coding: c.1865C>T
MANE Select: NM_001017437
dbSNP: rs753475863
Type: single nucleotide variant
Location: chr22:30376266 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.73
Residue 622: the 'disordered' region

Full CCDC157 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC157 p.Arg45Leu Uncertain significance ★★ ⚠ same type
CCDC157 p.Ala223Pro Uncertain significance ★ ⚠ same type
CCDC157 p.Ala292Val Uncertain significance ★ ⚠ same type
CCDC157 p.Ala300Thr Uncertain significance ★ ⚠ same type
CCDC157 p.Ala317Thr Uncertain significance ★ ⚠ same type
CCDC157 p.Ala324Ser Uncertain significance ★ ⚠ same type
CCDC157 p.Ala32Thr Uncertain significance ★ ⚠ same type
CCDC157 p.Ala389Val 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/ccdc157-p-pro622leu (accessed [today's date]).

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