Is SYNRG p.Arg1257Thr (c.3770G>C) pathogenic?

SYNRG p.Arg1257Thr (c.3770G>C) is classified Uncertain significance in SYNRG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely pathogenic (0.95); Ultra-rare (popmax 0.02%, afr).

How common is SYNRG p.Arg1257Thr (c.3770G>C) in the general population?

SYNRG p.Arg1257Thr (c.3770G>C) is ultra-rare (popmax 0.02%, afr) (gnomAD).

What do computational predictors say about SYNRG p.Arg1257Thr (c.3770G>C)?

AlphaMissense predicts likely pathogenic (score 0.95) — an in-silico prediction, not a clinical call.

SYNRG p.Arg1257Thr

c.3770G>C · VCV3964679

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.95 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.95	likely pathogenic · top 8% in SYNRG
REVEL	0.258	benign-leaning
SaProt	LLR -5.39	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 66 kb · p 8.4e-08 · regional, not allelic
Overall
CADD	23.4	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 0.02% African / African-American · 15/74,870 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0099%

Overall 0.00105% 17/1,613,940 alleles · ultra-rare exomes 6/1,461,870 · genomes 11/152,070 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.02%	4,991
Admixed American	0.00167%	60,000
European (non-Finnish)	8.47e-05%	1,180,025

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: SYNRG
Protein: p.Arg1257Thr
Coding: c.3770G>C
MANE Select: NM_007247
Type: single nucleotide variant
Location: chr17:37520545 (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-arg1257thr (accessed [today's date]).

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