Is PARL p.Pro92Ser (c.274C>T) pathogenic?

PARL p.Pro92Ser (c.274C>T) is classified Uncertain significance in PARL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-05). AlphaMissense: likely benign (0.0749); Very rare (popmax 0.00415%, nfe).

How common is PARL p.Pro92Ser (c.274C>T) in the general population?

PARL p.Pro92Ser (c.274C>T) is very rare (popmax 0.00415%, nfe) (gnomAD).

What do computational predictors say about PARL p.Pro92Ser (c.274C>T)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

PARL p.Pro92Ser

c.274C>T · VCV3885661

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.383	indeterminate
SaProt	LLR -5.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 55 kb · p 0.19 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00415% European (non-Finnish) · 49/1,179,870 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.007% 113/1,613,772 alleles · very rare exomes 98/1,461,632 · genomes 15/152,140 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.179%	558
Remaining individualsnot grpmax-eligible	0.016%	6,248
European (non-Finnish)grpmax	0.00415%	24,079
Admixed American	0.00167%	59,996

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PARL
Protein: p.Pro92Ser
Coding: c.274C>T
MANE Select: NM_018622
Type: single nucleotide variant
Location: chr3:183867912 (GRCh38)
Gene constraint: LOEUF 1.254 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.67

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

Similar variants

PARL p.Pro92Leu Uncertain significance ★ ⚠ same residue
PARL p.Ala117Thr Uncertain significance ★ same type
PARL p.Ala223Val Uncertain significance ★ ⚠ same type
PARL p.Ala297Gly Uncertain significance ★ ⚠ same type
PARL p.Ala2Glu Uncertain significance ★ ⚠ same type
PARL p.Ala308Val Uncertain significance ★ ⚠ same type
PARL p.Arg167Trp Uncertain significance ★ same type
PARL p.Arg190Gln 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/parl-p-pro92ser (accessed [today's date]).

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