Is ACD p.His206Pro (c.617A>C) pathogenic?

ACD p.His206Pro (c.617A>C) is classified Conflicting classifications of pathogenicity in ACD (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-10-22). AlphaMissense: likely benign (0.0794); Rare (popmax 0.33%, mid); Associated with ACD-related short telomere syndrome.

What condition is associated with ACD p.His206Pro (c.617A>C)?

ACD p.His206Pro (c.617A>C) is associated with ACD-related short telomere syndrome, dyskeratosis congenita, autosomal dominant 6 (ClinVar).

How common is ACD p.His206Pro (c.617A>C) in the general population?

ACD p.His206Pro (c.617A>C) is rare (popmax 0.33%, mid) (gnomAD).

What do computational predictors say about ACD p.His206Pro (c.617A>C)?

AlphaMissense predicts likely benign (score 0.0794) — an in-silico prediction, not a clinical call.

ACD p.His206Pro

c.617A>C · rs755371076 · VCV1058605

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0794 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.33%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACD-related short telomere syndrome

Computational evidence

Protein change
AlphaMissense	0.0794	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -3.94	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 -0.062	GERP -2.9, phastCons 0.071
Regional constraint	o/e 0.89	unconstrained · MANE · 2,611 bp · p 0.011 · regional, not allelic
Overall
CADD	5.905	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 0.33% Middle Eastern · 20/6,062 alleles

Filtering AF 0.219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.183%

Overall 0.00341% 55/1,613,686 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.33%	303
Remaining individualsnot grpmax-eligible	0.0096%	10,416
African / African-American	0.008%	12,497
Admixed American	0.005%	19,998
South Asian	0.00329%	30,356
European (non-Finnish)	0.00144%	69,409

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.His206Pro
Coding: c.617A>C
MANE Select: NM_001082486
dbSNP: rs755371076
Type: single nucleotide variant
Location: chr16:67658956 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 63.09 · 28 PDB
Residue 206: the 'interaction with pot1' region; an α-helix

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

Disease context

Also linked: dyskeratosis congenita, autosomal dominant 6

Similar variants

ACD p.His206Gln Uncertain significance ★ ⚠ same residue
ACD p.His206= Likely benign ★ 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-his206pro (accessed [today's date]).

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