Is DDIAS p.Ser749Phe (c.2246C>T) pathogenic?

DDIAS p.Ser749Phe (c.2246C>T) is classified Uncertain significance in DDIAS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-31). AlphaMissense: likely benign (0.1027); Ultra-rare (popmax 0.0264%, sas).

How common is DDIAS p.Ser749Phe (c.2246C>T) in the general population?

DDIAS p.Ser749Phe (c.2246C>T) is ultra-rare (popmax 0.0264%, sas) (gnomAD).

What do computational predictors say about DDIAS p.Ser749Phe (c.2246C>T)?

AlphaMissense predicts likely benign (score 0.1027) — an in-silico prediction, not a clinical call.

DDIAS p.Ser749Phe

c.2246C>T · rs760885843 · VCV2532091

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1027 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0264%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1027	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -8.26	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 2	GERP -0.33, phastCons 0.49
Regional constraint	o/e 0.92	unconstrained · MANE · 20 kb · p 0.0043 · regional, not allelic
Overall
CADD	17.77	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 0.0264% South Asian · 24/91,006 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00239% 35/1,461,616 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0264%	3,792
Admixed American	0.00167%	59,990
Remaining individualsnot grpmax-eligible	0.0016%	62,496
European (non-Finnish)	0.000763%	131,103

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: DDIAS
Protein: p.Ser749Phe
Coding: c.2246C>T
MANE Select: NM_145018
dbSNP: rs760885843
Type: single nucleotide variant
Location: chr11:82933584 (GRCh38)
Gene constraint: LOEUF 1.118 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 43.31

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

Similar variants

DDIAS p.Ala14Thr Uncertain significance ★ ⚠ same type
DDIAS p.Ala260Val Uncertain significance ★ ⚠ same type
DDIAS p.Ala389Ser Uncertain significance ★ ⚠ same type
DDIAS p.Ala402Val Uncertain significance ★ ⚠ same type
DDIAS p.Ala438Gly Uncertain significance ★ ⚠ same type
DDIAS p.Ala478Asp Uncertain significance ★ ⚠ same type
DDIAS p.Ala675Gly Uncertain significance ★ ⚠ same type
DDIAS p.Ala927Val 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/ddias-p-ser749phe (accessed [today's date]).

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