Is PER3 p.Arg374Trp (c.1120C>T) pathogenic?

PER3 p.Arg374Trp (c.1120C>T) is classified Uncertain significance in PER3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely benign (0.238); Ultra-rare (popmax 0.0517%, amr).

How common is PER3 p.Arg374Trp (c.1120C>T) in the general population?

PER3 p.Arg374Trp (c.1120C>T) is ultra-rare (popmax 0.0517%, amr) (gnomAD).

What do computational predictors say about PER3 p.Arg374Trp (c.1120C>T)?

AlphaMissense predicts likely benign (score 0.238) — an in-silico prediction, not a clinical call.

PER3 p.Arg374Trp

c.1120C>T · rs199945897 · VCV3211449

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.238 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0517%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.238	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -12.42	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.98 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1	GERP 2.1, phastCons 0.001
Regional constraint	o/e 1.09	unconstrained · MANE · 45 kb · p 0.002 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R373W vs ClinVar R374W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0517% Admixed American · 31/59,910 alleles

Filtering AF 0.0374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.00329% 53/1,613,224 alleles · ultra-rare exomes 39/1,460,980 · genomes 14/152,244 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0517%	1,933
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,864
Remaining individualsnot grpmax-eligible	0.00961%	10,408
African / African-American	0.00667%	14,999
East Asian	0.00223%	44,864
South Asian	0.0022%	45,431
European (non-Finnish)	0.000424%	235,913

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: PER3
Protein: p.Arg374Trp
Coding: c.1120C>T
MANE Select: NM_001377275
dbSNP: rs199945897
Type: single nucleotide variant
Location: chr1:7803832 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.62
Residue 373 UniProt numbering: the pac domain

Full PER3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PER3 p.Arg157His Uncertain significance ★★ ⚠ same type
PER3 p.Asn572Thr Uncertain significance ★★ ⚠ same type
PER3 p.Ala980= Benign ★★ same type
PER3 p.Cys1185Ser Benign ★★ same type
PER3 p.Ile614= Benign ★★ same type
PER3 p.Leu937= Likely benign ★★ same type
PER3 p.Thr527Ala Likely benign ★★ same type
PER3 p.Thr983= Benign/Likely benign ★★ 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/per3-p-arg374trp (accessed [today's date]).

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