Is ACD p.Ser321Leu (c.962C>T) pathogenic?

ACD p.Ser321Leu (c.962C>T) is classified Uncertain significance in ACD (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.0937); Ultra-rare (popmax 0.0825%, mid); Associated with dyskeratosis congenita, autosomal dominant 6.

What condition is associated with ACD p.Ser321Leu (c.962C>T)?

ACD p.Ser321Leu (c.962C>T) is associated with dyskeratosis congenita, autosomal dominant 6 (ClinVar).

How common is ACD p.Ser321Leu (c.962C>T) in the general population?

ACD p.Ser321Leu (c.962C>T) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

What do computational predictors say about ACD p.Ser321Leu (c.962C>T)?

AlphaMissense predicts likely benign (score 0.0937) — an in-silico prediction, not a clinical call.

ACD p.Ser321Leu

c.962C>T · rs374925782 · VCV647101

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0937 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita, autosomal dominant 6

Computational evidence

Protein change
AlphaMissense	0.0937	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -7.02	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 4.8	GERP 0.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 2,611 bp · p 0.011 · regional, not allelic
Overall
CADD	20.9	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 0.0825% Middle Eastern · 5/6,062 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00762% 123/1,613,492 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.0176%	5,682
Admixed American	0.0117%	8,573
European (non-Finnish)	0.00788%	12,688
African / African-American	0.004%	25,015
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
South Asian	0.00329%	30,361

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.Ser321Leu
Coding: c.962C>T
MANE Select: NM_001082486
dbSNP: rs374925782
Type: single nucleotide variant
Location: chr16:67658230 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 63.09 · 28 PDB
Residue 321: 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.Ser321Thr 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
ACD c.-29C>A Uncertain significance ★★ same condition
ACD c.-29C>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-ser321leu (accessed [today's date]).

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