Is DNTT p.Asp280His (c.838G>C) pathogenic?

DNTT p.Asp280His (c.838G>C) is classified Likely benign in DNTT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-08-10). AlphaMissense: likely benign (0.1875); Rare (popmax 0.99%, mid).

How common is DNTT p.Asp280His (c.838G>C) in the general population?

DNTT p.Asp280His (c.838G>C) is rare (popmax 0.99%, mid) (gnomAD).

What do computational predictors say about DNTT p.Asp280His (c.838G>C)?

AlphaMissense predicts likely benign (score 0.1875) — an in-silico prediction, not a clinical call.

DNTT p.Asp280His

c.838G>C · rs41291616 · VCV791541

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1875 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.99%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1875	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -9.11	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 8.7	GERP 1.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 34 kb · p 0.13 · regional, not allelic
Overall
CADD	22.9	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 0.99% Middle Eastern · 60/6,058 alleles

Filtering AF 0.79% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.717%

Overall 0.507% 8,178/1,613,844 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.99%	101
European (non-Finnish)	0.585%	171
Admixed American	0.528%	189
Remaining individualsnot grpmax-eligible	0.483%	207
Finnishnot grpmax-eligible	0.348%	287
South Asian	0.258%	388
Ashkenazi Jewishnot grpmax-eligible	0.176%	569
African / African-American	0.112%	893

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: DNTT
Protein: p.Asp280His
Coding: c.838G>C
MANE Select: NM_004088
dbSNP: rs41291616
Type: single nucleotide variant
Location: chr10:96324353 (GRCh38)
Gene constraint: LOEUF 0.942 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.49 · 2 PDB
Residue 280: the 'mediates interaction with dnttip2' region

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

Similar variants

DNTT c.203+7C>G Benign ★★ same type
DNTT c.203+9G>A Benign ★★ same type
DNTT p.Ala90Val Benign ★★ same type
DNTT p.Glu244= Benign/Likely benign ★★ same type
DNTT p.Ala194Val Uncertain significance ★ ⚠ same type
DNTT p.Ala195Thr Uncertain significance ★ ⚠ same type
DNTT p.Ala21Val Uncertain significance ★ ⚠ same type
DNTT p.Ala239Ser 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/dntt-p-asp280his (accessed [today's date]).

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