Is CCDC136 p.Leu597Pro (c.1790T>C) pathogenic?

CCDC136 p.Leu597Pro (c.1790T>C) is classified Uncertain significance in CCDC136 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: ambiguous (0.443); Very rare (popmax 0.00815%, amr).

How common is CCDC136 p.Leu597Pro (c.1790T>C) in the general population?

CCDC136 p.Leu597Pro (c.1790T>C) is very rare (popmax 0.00815%, amr) (gnomAD).

What do computational predictors say about CCDC136 p.Leu597Pro (c.1790T>C)?

AlphaMissense predicts ambiguous (score 0.443) — an in-silico prediction, not a clinical call.

CCDC136 p.Leu597Pro

c.1790T>C · VCV4220445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.443 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00815%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.443	ambiguous
REVEL	0.188	benign-leaning
SaProt	LLR -7.62	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	phastCons 0.98
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 3e-06 · regional, not allelic
Overall
CADD	22.6	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 0.00815% Admixed American · 4/49,104 alleles

Filtering AF 0.0027% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00158%

Overall 0.000392% 6/1,528,866 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00815%	12,276
European (non-Finnish)	0.000176%	567,985

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: CCDC136
Protein: p.Leu597Pro
Coding: c.1790T>C
MANE Select: NM_022742
Type: single nucleotide variant
Location: chr7:128809634 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.24

Full CCDC136 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC136 p.Ala687= Benign ★★ same type
CCDC136 p.Asp218His Benign ★★ ⚠ same type
CCDC136 p.Glu1087= Benign ★★ same type
CCDC136 p.Glu1097Gly Likely benign ★★ ⚠ same type
CCDC136 p.Gly221= Benign ★★ same type
CCDC136 p.Gly980Arg Benign ★★ same type
CCDC136 p.Leu616= Benign ★★ same type
CCDC136 p.Val432Ile 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/ccdc136-p-leu597pro (accessed [today's date]).

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