Is GHRL p.Phe80Ser (c.239T>C) pathogenic?

GHRL p.Phe80Ser (c.239T>C) is classified Uncertain significance in GHRL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-14). AlphaMissense: ambiguous (0.5594); Ultra-rare (popmax 0.0667%, afr).

How common is GHRL p.Phe80Ser (c.239T>C) in the general population?

GHRL p.Phe80Ser (c.239T>C) is ultra-rare (popmax 0.0667%, afr) (gnomAD).

What do computational predictors say about GHRL p.Phe80Ser (c.239T>C)?

AlphaMissense predicts ambiguous (score 0.5594) — an in-silico prediction, not a clinical call.

GHRL p.Phe80Ser

c.239T>C · rs201358681 · VCV2381660

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5594 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5594	ambiguous
REVEL	0.286	benign-leaning
SaProt	LLR -6.82	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.7, phastCons 0.98
Regional constraint	o/e 1.36	unconstrained · MANE · 4,302 bp · p 2e-05 · regional, not allelic
Overall
CADD	22.2	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 0.0667% African / African-American · 50/74,980 alleles

Filtering AF 0.0519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0467%

Overall 0.00335% 54/1,609,724 alleles · ultra-rare exomes 27/1,457,410 · genomes 27/152,314 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0667%	1,500
Remaining individualsnot grpmax-eligible	0.00321%	31,167
Admixed American	0.00167%	60,002
European (non-Finnish)	8.5e-05%	1,176,028

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: GHRL
Protein: p.Phe80Ser
Coding: c.239T>C
MANE Select: NM_016362
dbSNP: rs201358681
Type: single nucleotide variant
Location: chr3:10286799 (GRCh38)
Gene constraint: LOEUF 1.822 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.12 · 4 PDB

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

Similar variants

GHRL c.109-36G>A Benign ★★ same type
GHRL c.226-286C>T Benign ★★ same type
GHRL c.226-313A>G Benign ★★ same type
GHRL c.334+138T>G Benign ★★ same type
GHRL p.Gln90Leu Benign ★★ same type
GHRL c.225+2T>G Uncertain significance ★ same type
GHRL c.-771G>A Uncertain significance ★ same type
GHRL c.-789C>T 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/ghrl-p-phe80ser (accessed [today's date]).

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