Is SYNCRIP p.Ile376Val (c.1126A>G) pathogenic?

SYNCRIP p.Ile376Val (c.1126A>G) is classified Likely benign in SYNCRIP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-12). AlphaMissense: likely benign (0.0882); Very rare (popmax 0.00466%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SYNCRIP p.Ile376Val (c.1126A>G)?

SYNCRIP p.Ile376Val (c.1126A>G) is associated with Inborn genetic diseases (ClinVar).

How common is SYNCRIP p.Ile376Val (c.1126A>G) in the general population?

SYNCRIP p.Ile376Val (c.1126A>G) is very rare (popmax 0.00466%, nfe) (gnomAD).

What do computational predictors say about SYNCRIP p.Ile376Val (c.1126A>G)?

AlphaMissense predicts likely benign (score 0.0882) — an in-silico prediction, not a clinical call.

SYNCRIP p.Ile376Val

c.1126A>G · VCV3451861

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0882 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00466%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0882	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -5.36	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 7.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 3,768 bp · p 3.9e-16 · regional, not allelic
Overall
CADD	20.3	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 0.00466% European (non-Finnish) · 55/1,179,994 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.00366% 59/1,613,888 alleles · very rare exomes 56/1,461,682 · genomes 3/152,206 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00466%	21,454
Finnishnot grpmax-eligible	0.00312%	32,005
Remaining individualsnot grpmax-eligible	0.0016%	62,476
South Asian	0.0011%	91,066

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: SYNCRIP
Protein: p.Ile376Val
Coding: c.1126A>G
MANE Select: NM_006372
Type: single nucleotide variant
Location: chr6:85619300 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.83 · 4 PDB
Residue 376: the rrm 3 domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SYNCRIP p.Ala216Thr Uncertain significance ★★ same condition
SYNCRIP p.Asn243Ser Uncertain significance ★★ ⚠ same condition
SYNCRIP p.Pro440Leu Uncertain significance ★★ ⚠ same condition
SYNCRIP p.Pro508Leu Uncertain significance ★★ ⚠ same condition
SYNCRIP p.Ser116Gly Uncertain significance ★★ ⚠ same condition
SYNCRIP p.Glu612Val Likely benign ★★ ⚠ same condition
SYNCRIP p.Ala346Thr Uncertain significance ★ ⚠ same condition
SYNCRIP p.Ala357Val 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/syncrip-p-ile376val (accessed [today's date]).

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