Is DDN p.Ala553Val (c.1658C>T) pathogenic?

DDN p.Ala553Val (c.1658C>T) is classified Likely benign in DDN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: likely benign (0.0748); Ultra-rare (popmax 0.068%, mid).

How common is DDN p.Ala553Val (c.1658C>T) in the general population?

DDN p.Ala553Val (c.1658C>T) is ultra-rare (popmax 0.068%, mid) (gnomAD).

What do computational predictors say about DDN p.Ala553Val (c.1658C>T)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

DDN p.Ala553Val

c.1658C>T · VCV4010038

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.068%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0748	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -6.35	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 0.097	GERP -1.6
Regional constraint	o/e 0.96	unconstrained · MANE · 2,544 bp · p 0.18 · regional, not allelic
Overall
CADD	1.278	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 0.068% Middle Eastern · 4/5,882 alleles

Filtering AF 0.0232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0139%

Overall 0.00334% 53/1,585,788 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.068%	1,470
Ashkenazi Jewishnot grpmax-eligible	0.0181%	5,514
Remaining individualsnot grpmax-eligible	0.0114%	8,741
African / African-American	0.00673%	14,866
Admixed American	0.00525%	19,063
European (non-Finnish)	0.00249%	40,201

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: DDN
Protein: p.Ala553Val
Coding: c.1658C>T
MANE Select: NM_015086
Type: single nucleotide variant
Location: chr12:48997218 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 46.28
Residue 553: the 'interaction with cd2ap and nphs1' region; the 'disordered' region

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

Similar variants

DDN p.Ala553Asp Uncertain significance ★ ⚠ same residue
DDN p.Ala553Gly Uncertain significance ★ ⚠ same residue
DDN p.Glu661Gly Benign ★★ same type
DDN p.Pro358Arg Benign ★★ same type
DDN p.Ala154Thr Uncertain significance ★ ⚠ same type
DDN p.Ala169Val Uncertain significance ★ ⚠ same type
DDN p.Ala174Glu Uncertain significance ★ ⚠ same type
DDN p.Ala179Thr Uncertain significance ★ ⚠ same type

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/ddn-p-ala553val (accessed [today's date]).

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