Is DLD p.Thr165Met (c.494C>T) pathogenic?

DLD p.Thr165Met (c.494C>T) is classified Uncertain significance in DLD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-26). AlphaMissense: likely benign (0.1116); Very rare (popmax 0.00831%, nfe).

How common is DLD p.Thr165Met (c.494C>T) in the general population?

DLD p.Thr165Met (c.494C>T) is very rare (popmax 0.00831%, nfe) (gnomAD).

What do computational predictors say about DLD p.Thr165Met (c.494C>T)?

AlphaMissense predicts likely benign (score 0.1116) — an in-silico prediction, not a clinical call.

DLD p.Thr165Met

c.494C>T · rs748960915 · VCV2682992

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1116 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00831%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1116	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -11.51	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.15	GERP -2.8, phastCons 0.003
Regional constraint	o/e 0.89	unconstrained · MANE · 28 kb · p 0.0061 · regional, not allelic
Overall
CADD	16.16	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 0.00831% European (non-Finnish) · 98/1,179,784 alleles

Filtering AF 0.00697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00663% 107/1,613,628 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00831%	12,039
Remaining individualsnot grpmax-eligible	0.0064%	15,617
African / African-American	0.00534%	18,721
South Asian	0.0011%	91,072

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: DLD
Protein: p.Thr165Met
Coding: c.494C>T
MANE Select: NM_000108
dbSNP: rs748960915
Type: single nucleotide variant
Location: chr7:107905416 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB
Residue 165: a β-strand

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

Similar variants

DLD p.Thr165= Likely benign ★★ same residue
DLD p.Thr165fs Likely pathogenic ★ same residue
DLD c.1464+1G>A Pathogenic/Likely pathogenic ★★ same type
DLD c.198+1G>T Likely pathogenic ★★ same type
DLD c.39+1G>A Likely pathogenic ★★ same type
DLD c.40-2A>G Likely pathogenic ★★ same type
DLD c.583-1G>C Likely pathogenic ★★ same type
DLD c.684+1G>T Likely 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/dld-p-thr165met (accessed [today's date]).

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