Is CCDC136 p.Arg421Trp (c.1261C>T) pathogenic?

CCDC136 p.Arg421Trp (c.1261C>T) is classified Uncertain significance in CCDC136 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-24). AlphaMissense: likely benign (0.1752); Very rare (popmax 0.00669%, amr).

How common is CCDC136 p.Arg421Trp (c.1261C>T) in the general population?

CCDC136 p.Arg421Trp (c.1261C>T) is very rare (popmax 0.00669%, amr) (gnomAD).

What do computational predictors say about CCDC136 p.Arg421Trp (c.1261C>T)?

AlphaMissense predicts likely benign (score 0.1752) — an in-silico prediction, not a clinical call.

CCDC136 p.Arg421Trp

c.1261C>T · VCV3263843

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1752 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1752	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -10.64	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.86 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.4	phastCons 0.98
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 3e-06 · regional, not allelic
Overall
CADD	34.0	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 0.00669% Admixed American · 4/59,802 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00211% 34/1,609,880 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00669%	14,950
African / African-American	0.00267%	37,410
European (non-Finnish)	0.00229%	43,669
Remaining individualsnot grpmax-eligible	0.00161%	62,222

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.Arg421Trp
Coding: c.1261C>T
MANE Select: NM_022742
Type: single nucleotide variant
Location: chr7:128806700 (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-arg421trp (accessed [today's date]).

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