Is LIN28A p.Pro182Ala (c.544C>G) pathogenic?

LIN28A p.Pro182Ala (c.544C>G) is classified Uncertain significance in LIN28A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-26). AlphaMissense: likely benign (0.0606); Ultra-rare (popmax 0.0165%, mid).

How common is LIN28A p.Pro182Ala (c.544C>G) in the general population?

LIN28A p.Pro182Ala (c.544C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about LIN28A p.Pro182Ala (c.544C>G)?

AlphaMissense predicts likely benign (score 0.0606) — an in-silico prediction, not a clinical call.

LIN28A p.Pro182Ala

c.544C>G · rs200820472 · VCV3118919

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0606 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0606	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -6.27	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 1.8	GERP 0.92, phastCons 0.93
Regional constraint	o/e 1.19	unconstrained · MANE · 94 bp · p 0.24 · regional, not allelic
Overall
CADD	21.6	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00828%

Overall 0.00824% 133/1,614,142 alleles · ultra-rare exomes 128/1,461,882 · genomes 5/152,260 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.0117%	8,574
European (non-Finnish)	0.0103%	9,672
Remaining individualsnot grpmax-eligible	0.0016%	62,508
Finnishnot grpmax-eligible	0.00156%	64,026
African / African-American	0.00133%	75,024

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: LIN28A
Protein: p.Pro182Ala
Coding: c.544C>G
MANE Select: NM_024674
dbSNP: rs200820472
Type: single nucleotide variant
Location: chr1:26426372 (GRCh38)
Gene constraint: LOEUF 0.831 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 76.53 · 8 PDB
Residue 182: the 'disordered' region

Full LIN28A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LIN28A p.Leu176Val Uncertain significance ★★ ⚠ same type
LIN28A p.Ala29= Benign ★★ same type
LIN28A p.Ala16Thr Uncertain significance ★ ⚠ same type
LIN28A p.Ala32Thr Uncertain significance ★ ⚠ same type
LIN28A p.Ala32Val Uncertain significance ★ ⚠ same type
LIN28A p.Ala92Ser Uncertain significance ★ ⚠ same type
LIN28A p.Arg123Gln Uncertain significance ★ ⚠ same type
LIN28A p.Arg192Gln 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/lin28a-p-pro182ala (accessed [today's date]).

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