Is ACD c.645+2T>C pathogenic?

ACD c.645+2T>C is classified Uncertain significance in ACD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-04). Very rare (popmax 0.00373%, nfe); Associated with dyskeratosis congenita, autosomal dominant 6.

What condition is associated with ACD c.645+2T>C?

ACD c.645+2T>C is associated with dyskeratosis congenita, autosomal dominant 6 (ClinVar).

How common is ACD c.645+2T>C in the general population?

ACD c.645+2T>C is very rare (popmax 0.00373%, nfe) (gnomAD).

ACD c.645+2T>C

rs774178147 · VCV1802891

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Conditions

dyskeratosis congenita, autosomal dominant 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.98	donor loss · deltas
Pangolin	Δ0.84	loss · gain 0.14 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Non-coding constraint	Z 2.86	1 kb window · o/e 0.83 · regional · uncalibrated
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00373% European (non-Finnish) · 44/1,179,746 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00316% 51/1,613,410 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,493
European (non-Finnish)grpmax	0.00373%	26,812
Finnishnot grpmax-eligible	0.00314%	31,896

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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
Coding: c.645+2T>C
MANE Select: NM_001082486
dbSNP: rs774178147
Type: single nucleotide variant
Location: chr16:67658926 (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

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

Similar variants

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
ACD c.-36C>G 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-c-645-plus-2t-c (accessed [today's date]).

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