Is ACD p.Val186Met (c.556G>A) pathogenic?

ACD p.Val186Met (c.556G>A) is classified Uncertain significance in ACD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely benign (0.234); Very rare (popmax 0.00659%, sas); Associated with dyskeratosis congenita, autosomal dominant 6.

What condition is associated with ACD p.Val186Met (c.556G>A)?

ACD p.Val186Met (c.556G>A) is associated with dyskeratosis congenita, autosomal dominant 6 (ClinVar).

How common is ACD p.Val186Met (c.556G>A) in the general population?

ACD p.Val186Met (c.556G>A) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about ACD p.Val186Met (c.556G>A)?

AlphaMissense predicts likely benign (score 0.234) — an in-silico prediction, not a clinical call.

ACD p.Val186Met

c.556G>A · rs780989111 · VCV2736368

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.234 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita, autosomal dominant 6

Computational evidence

Protein change
AlphaMissense	0.234	likely benign
REVEL	0.669	pathogenic-leaning
SaProt	LLR -6.81	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.41, phastCons 0.067
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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,090 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00285% 46/1,613,816 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,182
European (non-Finnish)	0.00331%	30,257
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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.Val186Met
Coding: c.556G>A
MANE Select: NM_001082486
dbSNP: rs780989111
Type: single nucleotide variant
Location: chr16:67659017 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 63.09 · 28 PDB
Residue 186: the 'interaction with pot1' region; an α-helix

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.Val186= Likely benign ★★ same residue
ACD p.Val186Leu 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

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-val186met (accessed [today's date]).

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