Is DISP1 p.Arg331Thr (c.992G>C) pathogenic?

DISP1 p.Arg331Thr (c.992G>C) is classified Uncertain significance in DISP1 (ClinVar, Single submitter, 2 submitters; last evaluated 2020-04-26). AlphaMissense: likely pathogenic (0.9276); Very rare (popmax 0.00333%, amr); Associated with DISP1-related Holoprosencephaly.

What condition is associated with DISP1 p.Arg331Thr (c.992G>C)?

DISP1 p.Arg331Thr (c.992G>C) is associated with DISP1-related Holoprosencephaly (ClinVar).

How common is DISP1 p.Arg331Thr (c.992G>C) in the general population?

DISP1 p.Arg331Thr (c.992G>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about DISP1 p.Arg331Thr (c.992G>C)?

AlphaMissense predicts likely pathogenic (score 0.9276) — an in-silico prediction, not a clinical call.

DISP1 p.Arg331Thr

c.992G>C · rs1679522239 · VCV1325509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9276 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DISP1-related Holoprosencephaly

Computational evidence

Protein change
AlphaMissense	0.9276	likely pathogenic
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -9.33	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.39	acceptor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 63 kb · p 8.4e-11 · regional, not allelic
Overall
CADD	26.0	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 0.00333% Admixed American · 2/59,990 alleles

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

Overall 0.00132% 2/152,072 alleles · very rare

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: DISP1
Protein: p.Arg331Thr
Coding: c.992G>C
MANE Select: NM_001377229
dbSNP: rs1679522239
Type: single nucleotide variant
Location: chr1:223002389 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 65.21 · 4 PDB
Residue 331: a UniProt-annotated variant site (in hpe10; uncertain significance; heterozygous variant inherited from unaffected parent)

Full DISP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DISP1-related Holoprosencephaly

Similar variants

DISP1 p.Val206Gly Uncertain significance ★★ ⚠ same condition
DISP1 p.Arg703Ter Uncertain significance ★ same condition
DISP1 p.Asp587His Uncertain significance ★ ⚠ same condition
DISP1 p.Cys865Ser Uncertain significance ★ ⚠ same condition
DISP1 p.Thr788Ala Uncertain significance ★ ⚠ same condition
DISP1 p.Val375Ile Uncertain significance ★ ⚠ same condition
DISP1 p.Gln1320Glu Uncertain significance ⚠ same condition
DISP1 p.Gly1047Ser Uncertain significance ⚠ same condition

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/disp1-p-arg331thr (accessed [today's date]).

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