Is ACD p.Ser274Ile (c.821G>T) pathogenic?

ACD p.Ser274Ile (c.821G>T) is classified Uncertain significance in ACD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-25). AlphaMissense: likely benign (0.1191); Absent from gnomAD v4.1; Associated with dyskeratosis congenita, autosomal dominant 6.

What condition is associated with ACD p.Ser274Ile (c.821G>T)?

ACD p.Ser274Ile (c.821G>T) is associated with dyskeratosis congenita, autosomal dominant 6 (ClinVar).

How common is ACD p.Ser274Ile (c.821G>T) in the general population?

ACD p.Ser274Ile (c.821G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACD p.Ser274Ile (c.821G>T)?

AlphaMissense predicts likely benign (score 0.1191) — an in-silico prediction, not a clinical call.

ACD p.Ser274Ile

c.821G>T · VCV3623642

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1191 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,566,176)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita, autosomal dominant 6

Computational evidence

Protein change
AlphaMissense	0.1191	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -8.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.52	acceptor gain · deltas
Pangolin	Δ0.23	loss · gain 0.06 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP -0.6	GERP -0.93
Regional constraint	o/e 0.89	unconstrained · MANE · 2,611 bp · p 0.011 · regional, not allelic
Overall
CADD	21.0	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

No allele count reported in gnomAD v4.1 (AN 1,566,176). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ACD
Protein: p.Ser274Ile
Coding: c.821G>T
MANE Select: NM_001082486
Type: single nucleotide variant
Location: chr16:67658563 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 63.09 · 28 PDB
Residue 274: 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 p.Ser274Asn Uncertain significance ★★ ⚠ same residue
ACD p.Ser274Gly Uncertain significance ★★ ⚠ same residue
ACD p.Ser274Arg Uncertain significance ★ ⚠ same residue
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

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-ser274ile (accessed [today's date]).

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