Is SYNRG p.Val1249Met (c.3745G>A) pathogenic?

SYNRG p.Val1249Met (c.3745G>A) is classified Uncertain significance in SYNRG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely pathogenic (0.8887); Absent from gnomAD v4.1.

How common is SYNRG p.Val1249Met (c.3745G>A) in the general population?

SYNRG p.Val1249Met (c.3745G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SYNRG p.Val1249Met (c.3745G>A)?

AlphaMissense predicts likely pathogenic (score 0.8887) — an in-silico prediction, not a clinical call.

SYNRG p.Val1249Met

c.3745G>A · VCV4591979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8887 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8887	likely pathogenic
REVEL	0.222	benign-leaning
SaProt	LLR -4.61	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 66 kb · p 8.4e-08 · regional, not allelic
Overall
CADD	25.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SYNRG
Protein: p.Val1249Met
Coding: c.3745G>A
MANE Select: NM_007247
Type: single nucleotide variant
Location: chr17:37520570 (GRCh38)
Gene constraint: LOEUF 0.38 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 48.74 · 1 PDB

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

Similar variants

SYNRG c.372-1G>A Uncertain significance ★ same type
SYNRG c.3813+5G>A Uncertain significance ★ same type
SYNRG p.Ala1246Val Uncertain significance ★ ⚠ same type
SYNRG p.Ala1291Thr Uncertain significance ★ ⚠ same type
SYNRG p.Ala15Thr Uncertain significance ★ ⚠ same type
SYNRG p.Ala171Val Uncertain significance ★ ⚠ same type
SYNRG p.Ala17Val Uncertain significance ★ ⚠ same type
SYNRG p.Ala261Thr 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/synrg-p-val1249met (accessed [today's date]).

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