Is ACD p.Pro136Leu (c.407C>T) pathogenic?

ACD p.Pro136Leu (c.407C>T) is classified Uncertain significance in ACD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-02). AlphaMissense: likely benign (0.0777); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ACD p.Pro136Leu (c.407C>T)?

ACD p.Pro136Leu (c.407C>T) is associated with Inborn genetic diseases, dyskeratosis congenita, autosomal dominant 6 (ClinVar).

How common is ACD p.Pro136Leu (c.407C>T) in the general population?

ACD p.Pro136Leu (c.407C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ACD p.Pro136Leu (c.407C>T)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

ACD p.Pro136Leu

c.407C>T · rs2543607819 · VCV3232680

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.008	strongly benign-leaning
SaProt	LLR -6.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	GERP -3.5
Regional constraint	o/e 0.89	unconstrained · MANE · 2,611 bp · p 0.011 · regional, not allelic
Overall
CADD	11.88	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 8.48e-05% European (non-Finnish) · 1/1,179,432 alleles

Overall 6.2e-05% 1/1,613,052 alleles · very rare exomes 1/1,460,722 · genomes 0/152,330 · joint denominator

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: ACD
Protein: p.Pro136Leu
Coding: c.407C>T
MANE Select: NM_001082486
dbSNP: rs2543607819
Type: single nucleotide variant
Location: chr16:67659543 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 63.09 · 28 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyskeratosis congenita, autosomal dominant 6

Similar variants

ACD c.645+2T>C Uncertain significance ★★ same condition
ACD c.99+5G>A Uncertain significance ★★ same condition
ACD c.-20C>T Uncertain significance ★★ same condition
ACD c.-24C>T Uncertain significance ★★ same condition
ACD c.-26T>G Uncertain significance ★★ same condition
ACD c.-29C>A Uncertain significance ★★ same condition
ACD c.-29C>T Uncertain significance ★★ same condition
ACD c.-30C>T Uncertain significance ★★ same condition

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/acd-p-pro136leu (accessed [today's date]).

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