Is SYNRG p.Val299Leu (c.895G>C) pathogenic?

SYNRG p.Val299Leu (c.895G>C) is classified Uncertain significance in SYNRG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-02). AlphaMissense: ambiguous (0.3715); Ultra-rare (popmax 0.0134%, afr).

How common is SYNRG p.Val299Leu (c.895G>C) in the general population?

SYNRG p.Val299Leu (c.895G>C) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

What do computational predictors say about SYNRG p.Val299Leu (c.895G>C)?

AlphaMissense predicts ambiguous (score 0.3715) — an in-silico prediction, not a clinical call.

SYNRG p.Val299Leu

c.895G>C · VCV3803579

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3715 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3715	ambiguous
REVEL	0.239	benign-leaning
SaProt	LLR -4.42	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, 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

Grpmax group 0.0134% African / African-American · 10/74,688 alleles

Filtering AF 0.00725% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00551%

Overall 0.000744% 12/1,613,356 alleles · ultra-rare exomes 4/1,461,474 · genomes 8/151,882 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0134%	7,469
Admixed American	0.00167%	59,958
Remaining individualsnot grpmax-eligible	0.0016%	62,462

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.Val299Leu
Coding: c.895G>C
MANE Select: NM_007247
Type: single nucleotide variant
Location: chr17:37576347 (GRCh38)
Gene constraint: LOEUF 0.38 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 48.74 · 1 PDB
Residue 299: the eh domain

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

Similar variants

SYNRG p.Val299Ala Uncertain significance ★ ⚠ same residue
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

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-val299leu (accessed [today's date]).

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