Is HERC2 p.Pro1371Ser (c.4111C>T) pathogenic?

HERC2 p.Pro1371Ser (c.4111C>T) is classified Uncertain significance in HERC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-10). AlphaMissense: likely benign (0.0691); Very rare (popmax 0.00348%, amr); Associated with Inborn genetic diseases.

What condition is associated with HERC2 p.Pro1371Ser (c.4111C>T)?

HERC2 p.Pro1371Ser (c.4111C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HERC2 p.Pro1371Ser (c.4111C>T) in the general population?

HERC2 p.Pro1371Ser (c.4111C>T) is very rare (popmax 0.00348%, amr) (gnomAD).

What do computational predictors say about HERC2 p.Pro1371Ser (c.4111C>T)?

AlphaMissense predicts likely benign (score 0.0691) — an in-silico prediction, not a clinical call.

HERC2 p.Pro1371Ser

c.4111C>T · rs748470314 · VCV2474663

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0691 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00348%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0691	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 927 bp · p 9.5e-10 · regional, not allelic
Overall
CADD	17.84	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00348% Admixed American · 2/57,454 alleles

Filtering AF 0.000577% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000216%

Overall 0.000549% 5/911,544 alleles · very rare exomes 5/770,966 · genomes 0/140,578 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00348%	28,727
East Asian	0.00242%	41,308
African / African-American	0.0017%	58,816
European (non-Finnish)	0.000183%	546,278

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: HERC2
Protein: p.Pro1371Ser
Coding: c.4111C>T
MANE Select: NM_004667
dbSNP: rs748470314
Type: single nucleotide variant
Location: chr15:28234177 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)

Full HERC2 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

HERC2 p.Ala1253Thr Uncertain significance ★★ same condition
HERC2 p.Ala1454Thr Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala200Val Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2331Val Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2458Thr Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2671Gly Uncertain significance ★★ same condition
HERC2 p.Ala2948Ser Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala3095Ser 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/herc2-p-pro1371ser (accessed [today's date]).

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