Is ACD p.Leu265Val (c.793C>G) pathogenic?

ACD p.Leu265Val (c.793C>G) is classified Uncertain significance in ACD (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-24). AlphaMissense: likely benign (0.0864); Rare (popmax 0.126%, eas); Associated with dyskeratosis congenita, autosomal dominant 6.

What condition is associated with ACD p.Leu265Val (c.793C>G)?

ACD p.Leu265Val (c.793C>G) is associated with dyskeratosis congenita, autosomal dominant 6 (ClinVar).

How common is ACD p.Leu265Val (c.793C>G) in the general population?

ACD p.Leu265Val (c.793C>G) is rare (popmax 0.126%, eas) (gnomAD).

What do computational predictors say about ACD p.Leu265Val (c.793C>G)?

AlphaMissense predicts likely benign (score 0.0864) — an in-silico prediction, not a clinical call.

ACD p.Leu265Val

c.793C>G · rs200934242 · VCV848065

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0864 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.126%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita, autosomal dominant 6

Computational evidence

Protein change
AlphaMissense	0.0864	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -7.12	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 1.4	GERP -2.5, phastCons 0.76
Regional constraint	o/e 0.89	unconstrained · MANE · 2,611 bp · p 0.011 · regional, not allelic
Overall
CADD	6.99	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 0.126% East Asian · 56/44,544 alleles

Filtering AF 0.0993% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0899%

Overall 0.00375% 59/1,574,150 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.126%	795
Remaining individualsnot grpmax-eligible	0.00165%	60,664
South Asian	0.00119%	84,232
European (non-Finnish)	8.63e-05%	1,158,792

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.Leu265Val
Coding: c.793C>G
MANE Select: NM_001082486
dbSNP: rs200934242
Type: single nucleotide variant
Location: chr16:67658591 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 63.09 · 28 PDB
Residue 265: the 'disordered' region

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

Disease context

dyskeratosis congenita, autosomal dominant 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-leu265val (accessed [today's date]).

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