Is DOC2A p.Thr171Met (c.512C>T) pathogenic?

DOC2A p.Thr171Met (c.512C>T) is classified Uncertain significance in DOC2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.0929); Very rare (popmax 0.00333%, amr).

How common is DOC2A p.Thr171Met (c.512C>T) in the general population?

DOC2A p.Thr171Met (c.512C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about DOC2A p.Thr171Met (c.512C>T)?

AlphaMissense predicts likely benign (score 0.0929) — an in-silico prediction, not a clinical call.

DOC2A p.Thr171Met

c.512C>T · VCV4243726

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0929	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -7.86	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 2.8	GERP -3.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 4,033 bp · p 0.00084 · regional, not allelic
Overall
CADD	19.42	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 0.00333% Admixed American · 2/59,992 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00062% 10/1,613,120 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,996
Remaining individualsnot grpmax-eligible	0.0032%	31,219
African / African-American	0.00267%	37,445
East Asian	0.00223%	44,890
European (non-Finnish)	0.000254%	393,174

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: DOC2A
Protein: p.Thr171Met
Coding: c.512C>T
MANE Select: NM_003586
Type: single nucleotide variant
Location: chr16:30009011 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 1 PDB
Residue 171: the c2 1 domain; an α-helix

Full DOC2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOC2A p.Thr171Ala Uncertain significance ★ ⚠ same residue
DOC2A c.715-4G>A Benign ★★ same type
DOC2A p.Gly48Ser Benign ★★ ⚠ same type
DOC2A p.Pro376Leu Benign ★★ ⚠ same type
DOC2A p.Pro392Ala Benign ★★ same type
DOC2A p.Ala125Thr Uncertain significance ★ ⚠ same type
DOC2A p.Ala227Val Uncertain significance ★ ⚠ same type
DOC2A p.Ala228Val 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/doc2a-p-thr171met (accessed [today's date]).

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