Is DHRS3 p.Arg249Met (c.746G>T) pathogenic?

DHRS3 p.Arg249Met (c.746G>T) is classified Uncertain significance in DHRS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-25). AlphaMissense: ambiguous (0.5317); Ultra-rare (popmax 0.033%, mid).

How common is DHRS3 p.Arg249Met (c.746G>T) in the general population?

DHRS3 p.Arg249Met (c.746G>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about DHRS3 p.Arg249Met (c.746G>T)?

AlphaMissense predicts ambiguous (score 0.5317) — an in-silico prediction, not a clinical call.

DHRS3 p.Arg249Met

c.746G>T · VCV3501477

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5317 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5317	ambiguous
REVEL	0.703	pathogenic-leaning
SaProt	LLR -9.87	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.82, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 49 kb · p 2.9e-05 · regional, not allelic
Overall
CADD	23.1	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 0.033% Middle Eastern · 2/6,056 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00403% 65/1,611,268 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,028
European (non-Finnish)	0.00517%	19,327
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,514
Remaining individualsnot grpmax-eligible	0.0016%	62,398

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: DHRS3
Protein: p.Arg249Met
Coding: c.746G>T
MANE Select: NM_004753
Type: single nucleotide variant
Location: chr1:12572806 (GRCh38)
Gene constraint: LOEUF 0.79 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 94.16

Full DHRS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DHRS3 p.Ala125Gly Uncertain significance ★ ⚠ same type
DHRS3 p.Ala125Thr Uncertain significance ★ ⚠ same type
DHRS3 p.Ala193Val Uncertain significance ★ ⚠ same type
DHRS3 p.Ala214Thr Uncertain significance ★ ⚠ same type
DHRS3 p.Ala269Gly Uncertain significance ★ ⚠ same type
DHRS3 p.Ala269Val Uncertain significance ★ ⚠ same type
DHRS3 p.Ala280Thr Uncertain significance ★ ⚠ same type
DHRS3 p.Ala63Ser 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/dhrs3-p-arg249met (accessed [today's date]).

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