Is DGAT1 p.Arg446Cys (c.1336C>T) pathogenic?

DGAT1 p.Arg446Cys (c.1336C>T) is classified Uncertain significance in DGAT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-07). AlphaMissense: likely benign (0.1199); Ultra-rare (popmax 0.0165%, mid).

How common is DGAT1 p.Arg446Cys (c.1336C>T) in the general population?

DGAT1 p.Arg446Cys (c.1336C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about DGAT1 p.Arg446Cys (c.1336C>T)?

AlphaMissense predicts likely benign (score 0.1199) — an in-silico prediction, not a clinical call.

DGAT1 p.Arg446Cys

c.1336C>T · rs782199338 · VCV1462841

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1199 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1199	likely benign
REVEL	0.478	indeterminate
SaProt	LLR -13.02	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.65 · evaluated, not missing
Pangolin	Δ0.21	gain · loss 0.12 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 9.7	GERP 0.53, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 10 kb · p 0.0026 · regional, not allelic
Overall
CADD	26.2	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 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00211% 34/1,612,088 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,788
Admixed American	0.00668%	14,973
East Asian	0.00446%	22,430
South Asian	0.0033%	30,291
European (non-Finnish)	0.00186%	53,621

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: DGAT1
Protein: p.Arg446Cys
Coding: c.1336C>T
MANE Select: NM_012079
dbSNP: rs782199338
Type: single nucleotide variant
Location: chr8:144316685 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.86 · 5 PDB
Residue 446: the 'mboat fold' region; an α-helix

Full DGAT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DGAT1 p.Arg446Leu Uncertain significance ★ ⚠ same residue
DGAT1 p.Arg446fs Uncertain significance ★ same residue
DGAT1 p.Arg446His Uncertain significance ★ same residue
DGAT1 c.1094+2T>C Pathogenic/Likely pathogenic ★★ same type
DGAT1 c.1160+1G>A Likely pathogenic ★★ same type
DGAT1 c.574+1G>T Likely pathogenic ★★ same type
DGAT1 c.676+1G>A Likely pathogenic ★★ same type
DGAT1 c.751+2T>C Pathogenic ★★ 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/dgat1-p-arg446cys (accessed [today's date]).

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