Is SYNCRIP p.Ala216Thr (c.646G>A) pathogenic?

SYNCRIP p.Ala216Thr (c.646G>A) is classified Uncertain significance in SYNCRIP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-10). AlphaMissense: ambiguous (0.5508); Very rare (popmax 0.000679%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SYNCRIP p.Ala216Thr (c.646G>A)?

SYNCRIP p.Ala216Thr (c.646G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SYNCRIP p.Ala216Thr (c.646G>A) in the general population?

SYNCRIP p.Ala216Thr (c.646G>A) is very rare (popmax 0.000679%, nfe) (gnomAD).

What do computational predictors say about SYNCRIP p.Ala216Thr (c.646G>A)?

AlphaMissense predicts ambiguous (score 0.5508) — an in-silico prediction, not a clinical call.

SYNCRIP p.Ala216Thr

c.646G>A · rs753313193 · VCV1343277

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5508 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000679%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5508	ambiguous
REVEL	0.617	indeterminate
SaProt	LLR -9.30	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 18 kb · p 2.8e-22 · regional, not allelic
Overall
CADD	29.3	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 0.000679% European (non-Finnish) · 8/1,178,928 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000497% 8/1,609,480 alleles · very rare exomes 8/1,457,150 · genomes 0/152,330 · joint denominator

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.Ala216Thr
Coding: c.646G>A
MANE Select: NM_006372
dbSNP: rs753313193
Type: single nucleotide variant
Location: chr6:85636987 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.83 · 4 PDB
Residue 216: the rrm 1 domain

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.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
SYNCRIP p.Ala567Val 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-ala216thr (accessed [today's date]).

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